The dates displayed for an article provide information on when various publication milestones were reached at the journal that has published the article activities on preceding journals at which the article was previously under consideration are not shown (for instance submission All content on this site: Copyright © 2025 Elsevier B.V. a Wilson County jury found Esteban San Miguel guilty of Sexual Assault of a Child and Aggravated Sexual Assault of a Child The jury sentenced Miguel to a maximum of 20 years for the Sexual Assault and 90 years for the Aggravated Sexual Assault He also faces a fine of $10,000 for each count "We hope this sentence serves as a manner of closure and peace for our victim and a warning to those who would seek to prey upon our children," said the Wilson County District Attorney in a Facebook statement Metrics details An Author Correction to this article was published on 18 March 2025 This article has been updated the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos Recent reports have shown that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs) offering a valuable in vitro model to study early placenta specification we demonstrate that the VGLL1 (vestigial-like family member 1) which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species Due to ethical considerations and difficulties in obtaining study material the genetic regulatory mechanisms underlying the formation of human TE and early cytotrophoblast remain unclear Mechanisms related to the onset of TE specification and most aspects of human TSC induction and maintenance remain in general poorly understood VGLL1 works through the interaction with TEAD4 by inducing histone H3 lysine 27 acetylation (H3K27ac) at target loci including cell cycle genes and TE/TSC-related genes we found that VGLL1 and TEAD4 cooperate with GATA3 and TFAP2C VGLL1 is highly expressed in primate TE but negligibly in mouse highlighting a potential interspecies difference in early placenta specification We have thus uncovered a key regulatory mechanism of human early placenta formation whose further characterization may facilitate a deeper understanding of both normal and abnormal developmental processes a Schematic depicting the generation of TELC-D5 from 4CL H9 ESCs with TE medium and the generation of TSCs from TELC-D5 cells with TSC medium VGLL1/TEAD4 knockdown (KD) and multiple types of sequencing were performed as indicated b Phase contrast images of 4CL H9 ESCs and TELCs at the indicated time points Representative of three independent experiments c Immunostaining images for pluripotency (NANOG and KLF17) and TE-enriched (GATA3 and VGLL1) genes in 4CL H9 ESCs (upper panels; scale bar 50 µm) and TELC-D5 cells (lower panels; scale bar Nuclei were counterstained with DAPI (blue) d Heatmap showing the expression of pluripotency and TE genes in bulk RNA-seq for the indicated conditions Example genes for each cluster are shown in the boxes e UMAP comparing the human embryonic day 4 (E4) to E14 stages with 4CL H9 ESCs and TELC-D5 cells All reference datasets used in this study are summarized in Methods f Bubble plot showing the frequency of expression and scaled average expression of representative genes in TELC-D5 cells and human embryo E4-E14 datasets g Volcano plot showing DEGs between 4CL H9 naïve ESCs and TELC-D5 cells DEGs higher in TELC-D5 cells (log2(fold change) > 1) are shown in red P value was calculated using the Wald test and adjusted for multiple testing using the Benjamini-Hochberg correction h RT-qPCR showing the expression of VGLL1 in 4CL H9 ESCs and TELC-D5 cells Data are presented as the mean ± standard error of the mean (SEM) of the fold-change compared to naive ESCs P value was calculated using a two-tailed unpaired Student’s t-test i Western blotting analysis for the indicated proteins in 4CL H9 ESCs Cell types were annotated by cluster-specific gene expression patterns j Violin plot showing the log-normalized expression of TE genes in different cell types at the mouse 16-cell stage k Left panel: the trajectory of the different cell types at the mouse 16-cell stage reveals two branches: pre-lineage to the TE branch and pre-lineage to the ICM branch Right panel: colors from dark blue to light blue indicate progression through the pseudotime l Expression patterns of TE genes along the pseudotime trajectory of cells at the mouse 16-cell stage These results indicate that VGLL1 may function as a TE induction regulator in primates a RT-qPCR showing the VGLL1 knockdown efficiency for 4CL H9 ESCs transduced with shVGLL1−2 or shVGLL1−4 compared to the shLuc control at day 5 of TELC differentiation b Western blotting analysis of the indicated proteins for 4CL H9 ESCs transduced with shVGLL1−2 or shVGLL1−4 compared to the shLuc control at day 5 of TELC differentiation c Representative phase contrast images of 4CL H9 ESCs transduced with shLuc (control) or shVGLL1 (2 and 4) at day 5 of TELC differentiation d Analysis of cell numbers for 4CL H9 ESCs transduced with shLuc shVGLL1−2 or shVGLL1−4 throughout the TELC induction time course e Heatmap showing the expression of pluripotency cell cycle and TE genes in 4CL H9 ESC-derived cells from the indicated conditions Example genes are shown for each cluster in the boxes f RT-qPCR showing the expression of TE-related genes for 4CL H9 ESCs transduced with shVGLL1−2 and shVGLL1−4 compared to the shLuc control at day 5 of TELC differentiation g Enriched GO terms for downregulated genes in 4CL H9 ESCs transduced with shVGLL1 compared to shLuc control at day 5 of TELC differentiation P value was calculated using a hypergeometric test (one-sided) and adjusted for multiple testing using the Benjamini-Hochberg correction h Enriched GO terms for upregulated genes in 4CL H9 ESCs transduced with shVGLL1 compared to shLuc control at day 5 of TELC differentiation i TA cloning followed by Sanger sequencing results showing homozygous deletion for VGLL1-knockout clones [clone 45 (C45) and clone 68 (C68)] j Western blotting analysis of VGLL1 expression in H9 WT and VGLL1-knockout clones at day 5 of TELC induction k Representative phase contrast images of H9 WT and VGLL1-knockout clones at day 5 of TELC induction l Analysis of cell numbers for H9 WT and VGLL1-knockout clones at day 5 of TELC induction m Heatmap showing the expression of pluripotency cell cycle and TE genes in bulk RNA-seq of H9 VGLL1-knockout clones compared to WT at day 5 of TELC induction n Enriched GO terms for downregulated genes in H9 VGLL1-knockout clones compared to WT at day 5 of TELC induction These findings demonstrate that VGLL1 is required for the induction of human TELCs regardless of the cell line or starting naive PSC medium we have demonstrated that VGLL1 is a critical regulator of the human naive PSC to TELC transition highlighting a major difference with mouse a Pie chart showing the distribution of VGLL1-binding sites throughout the annotated genomic locations in CUT&Tag of TELC-D5 cells differentiated from 4CL H9 ESCs b Venn diagram showing the overlap between downregulated genes in shVGLL1 compared to shLuc control and genes bound by VGLL1 at promoter sites in TELC-D5 differentiated from 4CL H9 ESCs c Enriched GO terms for genes bound by VGLL1 in TELC-D5 cells differentiated from 4CL H9 ESCs d Motif analysis using HOMER showing the significantly enriched DNA-binding motifs at VGLL1-bound sites in TELC-D5 cells differentiated from 4CL H9 ESCs P value was calculated using a hypergeometric test (one-sided) e Immunoprecipitation using lysates from TELC-D5 cells differentiated from 4CL H9 ESCs with anti-VGLL1 (left panel) or anti-TEAD4 (right panel) and subsequent Western blotting analysis with anti-TEAD4 f Pie chart showing the distribution of TEAD4-binding sites throughout the annotated genomic locations in TELC-D5 cells differentiated from 4CL H9 ESCs g Pie chart showing the distribution of YAP-binding sites throughout the annotated genomic locations in TELC-D5 cells differentiated from 4CL H9 ESCs h Venn diagram showing the overlap between VGLL1- TEAD4- and YAP-bound sites in CUT&Tag of TELC-D5 cells differentiated from 4CL H9 ESCs Representative cell cycle and TE genes corresponding to the overlapping regions are shown i Co-occupancy analysis by signal density pileups of VGLL1 TEAD4 and YAP peaks in CUT&Tag of TELC-D5 differentiated from 4CL H9 ESCs These results demonstrate that VGLL1 forms a complex with TEAD4 to regulate human TELC induction indicating that TEAD4 recruits all three co-factors to regulate human TELC induction while YAP was more restricted to the cytoplasm The distinct subcellular distribution further supports that TEAD4 interact less with YAP compared to VGLL1 These results demonstrate that VGLL1 functions as a strong co-factor for TEAD4 in addition to YAP and WWTR1 potentially adding more flexibility to safeguard TE development in human a Western blotting analysis for the indicated histone marks in 4CL H9 ESCs transduced with shLuc shVGLL1−2 or shVGLL1−4 at day 5 of TELC differentiation b Venn diagram showing the overlap between VGLL1- and TEAD4-bound sites and H3K27ac-enriched sites in CUT&Tag of TELC-D5 cells differentiated from 4CL H9 ESCs Representative cell cycle and TE genes corresponding to the overlapping regions are shown in the boxes TEAD4 and H3K27ac co-occupied genes in CUT&Tag of TELC-D5 differentiated from 4CL H9 ESCs d Co-occupancy analysis by signal density pileups of TEAD4 CUT&Tag peaks in 4CL H9 ESCs and TEAD4 CUT&Tag peaks in TELC-D5 cells differentiated from them Peaks were divided into three categories: naïve-specific e Signal intensity of H3K27ac in 4CL H9 ESCs (Naïve-H3K27ac) and TELC-D5 cells (TELC-D5-H3K27ac) and VGLL1 in TELC-D5 cells (TELC-D5-VGLL1) from the three categories defined in d f Venn diagram showing the overlap between VGLL1- and TEAD4-binding at H3K27ac-enriched sites in CUT&Tag with chromatin accessibility peaks (ATAC-seq) in TELC-D5 cells differentiated from H9 4CL naïve ESCs g Co-occupancy analysis by signal density pileups of VGLL1 H3K27ac CUT&Tag peaks and chromatin accessibility (ATAC-seq) peaks in TELC-D5 cells differentiated from 4CL H9 ESCs h Enriched GO terms for open chromatin genes (ATAC-seq) co-occupied by VGLL1 TEAD4 and H3K27ac (CUT&Tag) of TELC-D5 cells differentiated from 4CL H9 ESCs H3K27ac genomic enrichment peaks (CUT&Tag) and chromatin accessibility peaks (ATAC-seq) for representative TE gene loci of TELC-D5 cells differentiated from 4CL H9 ESCs j Signal intensity of TEAD4 at VGLL1-bound sites in WT and VGLL1-KO clone 68 (VGLL1-/--C68) at day 5 of TELC induction from 4CL H9 ESCs k Signal intensity of H3K27ac at VGLL1-binding sites in WT and VGLL1-KO clone 68 (VGLL1-/--C68) at day 5 of TELC induction from 4CL H9 ESCs l Signal intensity of chromatin openness at VGLL1-binding sites in WT and VGLL1-KO clone 68 (VGLL1-/--C68) at day 5 of TELC induction from 4CL H9 ESCs we observed that H3K27ac levels in naïve-specific TEAD4-bound genes were high in naïve ESCs but low in TELC-D5 cells H3K27ac levels in shared and TE-specific TEAD4-bound genes were increased in TELC-D5 cells we have demonstrated that TEAD4 becomes redistributed in TELCs compared to naïve PSCs and highlighted a link between VGLL1 recruitment by TEAD4 at target loci and chromatin opening through increased histone acetylation a Phase contrast images of 4CL H9 ESC-derived TSCs transduced with shLuc b Analysis of cell numbers for 4CL H9 ESC-derived TSCs transduced with shLuc c Heatmap showing the expression of pluripotency cell cycle and TSC genes for the indicated conditions d Enriched GO terms for downregulated genes in shVGLL1 compared to shLuc control in 4CL H9 ESC-derived TSCs e Immunoprecipitation using 4CL H9 ESC-derived TSC lysates with anti-VGLL1 (left panel) or anti-TEAD4 (right panel) and subsequent Western blotting with anti-TEAD4 f Western blotting for the indicated histone marks for shVGLL1-2 and shVGLL1-4 compared to the shLuc control in 4CL H9 ESC-derived TSCs H3K27ac genomic enrichment peaks (CUT&Tag) and chromatin accessibility peaks (ATAC-seq) for representative TSC genes loci in 4CL H9 ESC-derived TSCs h Co-occupancy analysis by signal density pileups of VGLL1 TEAD4 binding in 4CL H9 ESC-derived TELC-D5 cells and TSCs The three major groups are: group 1 (common between TELC-D5 and TSC) group 2 (TELC-specific) and group 3 (TSC-specific) TEAD4 and H3K27ac genomic enrichment peaks (CUT&Tag) in 4CL H9 ESC-derived TELC-D5 cells and TSCs for representative gene loci from group 2 (upper panel) and group 3 (lower panel) genes like PSG8 and PSG1 were co-bound by VGLL1 and TEAD4 in TSCs (group 3) We have demonstrated that the function of the tandem VGLL1-TEAD4 in controlling self-renewal and cell identity is conserved in both TELCs and TSCs derived from human naïve PSCs although there are differences between both cell types a Venn diagram showing the pairwise overlap between VGLL1- GATA3- and TFAP2C-bound sites in 4CL H9 ESC-derived TELC-D5 cells b Four-way venn diagram showing the overlap between VGLL1- and TFAP2C- bound sites in 4CL H9 ESC-derived TELC-D5 cells c Enriched GO terms for genes in Group 1 of panel b d Enriched GO terms for genes in group 2 of panel b e Motif analysis using HOMER showing the significantly enriched DNA-binding motifs at GATA3-binding sites in 4CL H9 ESC-derived TELC-D5 cells f Motif analysis using HOMER showing the significantly enriched DNA-binding motifs at TFAP2C-binding sites in 4CL H9 ESC-derived TELC-D5 cells GATA3 and TFAP2C binding in 4CL H9 ESC-derived TELC-D5 cells for representative TE loci which self-renew and can be differentiated into SCT and EVT While the developmental trajectories are reasonably well understood the key regulators and pathways underlying human TE formation and TSC maintenance are only beginning to be investigated and outstanding questions remain We show that VGLL1 expression substantially increases at the onset of both human and monkey TE specification consistent with the idea that stage-specific regulators often play critical roles in controlling cell fate UH10 iPSCs and TSCBT in this study is compliant with the ‘Guidance of the Ministry of Science and Technology for the Review and Approval of Human Genetic Resources’ and was approved by the ‘Life Science and Medical Ethics Committee’ of the Guangzhou Institutes of Biomedicine and Health under license number GIBH-LMEC2023-001-01(AL) 0.8 mM VPA (Vetec) and 5 µM Y-27632 (Axon) supplemented with 10 µM Y-27632 Human H9 ESCs were purchased from WiCell Research Institute Guangjin Pan (Guangzhou Institutes of Biomedicine and Health Takahiro Arima (Department of Informative Genetics Tohoku University Graduate School of Medicine) All cell lines were negative for mycoplasma human naïve PSCs were dissociated into single cells with a 1:1 mixture of 0.5 mM EDTA and TrypLE Express and plated at a density of 100,000 cell/well of 6-well plate on Geltrex in TE induction medium (1:1 mix of Neurobasal medium (Gibco) and DMEM/F12 (HyClone) supplemented with N2 (Gibco) and B27 (Gibco) 1 µM PD0325901 (Axon) and 1 µM A83-01 (Selleck)) for 5 days TELCs at day 5 were used for downstream analysis throughout this study TELCs at day 5 were dissociated into single cells with TrypLE and plated on Geltrex-coated 6-well plates at a 1:4-1:8 split ratio in TSC medium (DMEM/F12 supplemented with N2 and B27 Differentiation of TSCs toward EVT and SCT were performed as previously described60 TSCs were plated at a density of 70,000 cell/well on Geltrex-coated 6-well plates in EVT medium (TeSR™-E8 medium (STEM CELL) TSCs were plated at a density of 40,000 cell/per well on Geltrex-coated 6-well plates in SCT medium (TeSR™-E6 medium (STEM CELL) Medium was refreshed every two days during the course of 14 days A total of 1.25 × 104 TELCs or TSCs were seeded at day 0 per well of a 12-well plate or a total of 8 × 104 TELCs or 2.5 × 104 TSCs were seeded at day 0 per well of a 6-well plate The cell number was counted for 3 wells as triplicates using a hemocytometer Three independent experiments were performed Total RNA was isolated using RNAzol (MRC) based on the manufacturer’s instructions. RT-qPCR analysis was performed using the SYBR Premix ExTaq Kit (Takara, RR420A) with an ABI 7500 real-time PCR machine. All RT-qPCR primers are listed in Supplementary Table 4 Bulk RNA-seq library preparation and sequencing were performed at Berry Genomics Co cells were dissociated into single cells with a 1:1 mixture of 0.5 mM EDTA and TrypLE Express (Gibco) After passing through 70 μM cell strainers cell suspensions were converted to barcoded scRNA-seq libraries according to the manufacturer’s protocol Qubit ssDNA Assay kit (Thermo Fisher Scientific Q10212) was used to quantify the sequencing library concentration The resulting libraries were sequenced using a DIPSEQ T1 sequencer at the China National GeneBank (CNGB) in Shenzhen Cell versus gene UMIs (Unique Molecular Identifiers) count matrices were generated by PISA Public data were re-analyzed from E-MTAB-3929 Quality control for public datasets was processed according to their respective reference articles Four Seurat objects were merged and then three thousand genes that were repeatedly variable across datasets were selected by SelectIntegrationFeatures tools FindIntegrationAnchors was then performed with the settings reduction=rpca All datasets were finally integrated by IntegrateData with default parameters Principal components were selected by principal component analysis (PCA) Plots were generated using DimPlot and DotPlot Seurat object was processed using NormalizeData Dimension reduction started with PCA on 3,000 significantly variable genes and the first thirty principal components were selected as input for UMAP visualization Correlation analysis was based on the 10,000 significantly variable genes and cor () function in R (v3.6.2) Correlation heatmap were generated by pheatmap (v1.0.12) UMAP was used for visualization of public embryo scRNA-seq data (E-MTAB-3929 The single-cell trajectory was analyzed using the count matrix of public embryo scRNA-seq data by Monocle 2 (v4.1.0) DEGs between cell types were identified using FindAllMarkers function of Seurat package with the settings only.pos = TRUE logfc.threshold = 0.25 for trajectory analysis Dimensions were reduced by using the reduceDimension function with the method of DDRTree Lineage trajectory and branch points were then constructed Pre-lineage of the trajectory was chosen as the root Trajectory was plotted by plot_cell_trajectory function of Monocle 2 (v4.1.0) Expression patterns of key landmark genes along the trajectory were generated by plot_genes_branched_pseudotime function of Monocle 2 Plots were generated using stacked violin functions Data of bar charts are represented as mean ± standard error of the mean (SEM) Significance was tested using a two-tailed unpaired Student’s t-test The related P values or P value ranges are shown in the figure legend The number of replicates for each experiment is presented in the figure legends Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article A Correction to this paper has been published: https://doi.org/10.1038/s41467-025-57929-w Chromatin remodeler INO80 mediates trophectoderm permeability barrier to modulate morula-to-blastocyst transition Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2 Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos Roles and regulations of Hippo signaling during preimplantation mouse development Role of Hippo signaling pathway in early placental development The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass Mechanobiology of YAP and TAZ in physiology and disease Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the 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stem cells Modelling human blastocysts by reprogramming fibroblasts into iBlastoids Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids Modeling post-implantation stages of human development into early organogenesis with stem-cell-derived peri-gastruloids Complete human day 14 post-implantation embryo models from naive ES cells Self-patterning of human stem cells into post-implantation lineages Pluripotent stem cell-derived model of the post-implantation human embryo fastp: an ultra-fast all-in-one FASTQ preprocessor Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 ChIPseeker: an R/Bioconductor package for ChIP peak annotation Integrative analysis of ChIP-chip and ChIP-seq dataset ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data clusterProfiler: an R package for comparing biological themes among gene clusters Liu, C. et al. A portable and cost-effective microfluidic system for massively parallel singlecell transcriptome profiling. bioRxiv https://doi.org/10.1101/818450 (2019) Sambamba: fast processing of NGS alignment formats Comprehensive integration of single-cell data DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors Integrating single-cell transcriptomic data across different conditions Download references We thank all members of the Laboratory of Integrative Biology of the Guangzhou Institutes of Biomedicine and Health ang BGI research for their support We thank the instrument platform and the supercomputing center of the Guangzhou Institutes of Biomedicine and Health for their technical support We thank the CNGB for providing technical support This work was supported by the National Natural Science Foundation of China (32370848 the Guangdong Basic and Applied Basic Research Foundation (2021B1515120075 to M.A.E.) the Science and Technology Planning Project of Guangdong Province (2023B1212060050 to W.L.) the Guangzhou Science and Technology Foundation (2024A04J4702 and 202102020176 to W.L.) the CAS President’s International Fellowship Initiative (CAS-PIFI) for special experts (2020FSB0002 to M.A.M.) and the Foreign Expert Project-Young Talent Program (QN2022031001L to M.A.M.) These authors contributed equally: Yueli Yang State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Key Laboratory for Zoonosis Research of the Ministry of Education Guangzhou Institutes of Biomedicine and Health CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine Southern University of Science and Technology conceived the original idea and supervised this study conducted most of the experiments with help from Z.L. performed most of the bioinformatics analysis with help from J interpreted the data and wrote the manuscript with input from W.J. The authors declare no competing interests Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-024-44780-8 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science Early kidney structures made of mostly human cells have been grown in pig embryos for up to 28 days as part of efforts to grow human organs in other animals for transplants By Alice Klein A normal pig embryo (top row) and one with human kidney cells Kidneys that are more than 50 per cent human have started to grow in pigs for the first time after scientists created embryos made of human and pig cells and implanted them in sows for up to four weeks The research, conducted by Miguel Esteban at Guangzhou Institutes of Biomedicine and Health in China and his colleagues brings us a step closer to being able to grow human kidneys in other animals to address the shortage of organ donors Over 100,000 people in the US alone are currently waiting for a kidney transplant it may be possible to grow human kidneys in other species like pigs that have similar organ sizes and physiology to us Esteban and his colleagues explored this idea by creating pig embryos that couldn’t form kidneys of their own by disabling two key genes responsible for development of the organs they introduced human stem cells into the pig embryos hoping they would transform into kidney cells in the pigs and assemble into the relevant organs The human cells were genetically engineered to help them integrate in the foreign environment by increasing the expression of two pro-survival genes Get the most essential health and fitness news in your inbox every Saturday The researchers implanted over 1800 of these hybrid human-pig embryos in the reproductive tracts of 13 sows They only allowed the embryos to grow for 25 to 28 days before removing and analysing them because of ethical considerations including the possibility of producing pigs with human-like brains if the human cells spread beyond the kidneys Only five of the embryos successfully implanted but they were able to develop early kidney structures that were made of 50 to 65 per cent human cells and the rest pig cells “This is a very important study,” says Jun Wu at the University of Texas Southwestern Medical Center. Wu and his team reported their creation of the first human-pig embryos in 2017 but were only able to incorporate a very small proportion of human cells Esteban and his colleagues tracked where the human cells went in their pig embryos by tagging them with a red fluorescent marker They found that very few became incorporated in the early central nervous system or other organs Read more: Soya beans made more meat-like by adding genes for pig proteins The researchers have now received approval from their institute’s ethics committee to let such human-pig embryos develop for up to 35 days to see if the humanised kidneys continue to mature properly and to ensure minimal human cells end up in other organs “We will move forward step by step before reaching full term [of gestation],” says Esteban They are also looking at growing other human organs like the heart and liver in pigs Aside from this approach, other groups are working on ways to use pig-only organs for transplant into people. On 14 July, for example, surgeons at NYU Langone Health successfully transplanted a pig kidney into a brain-dead man The kidney came from an animal that had a single gene knocked out so that its organs wouldn’t trigger an immune reaction in human recipients A spokesperson for NYU Langone Health told New Scientist that the man’s kidney is still functioning properly almost two months later Wu believes that a combination of these two approaches – growing kidneys that are mostly human in pigs and also knocking out genes that might trigger immune reactions – may end up working best Cell Stem Cell DOI: 10.1016/j.stem.2023.08.003 NEW YORK (AP) — Anna Netrebko’s lawsuit against the Metropolitan Opera was narrowed to gender discrimination claims by a federal judge who agreed to dismiss the star soprano’s allegations of defamation breach of contract and discrimination because of national origin District Judge Analisa Nadine Torres in Manhattan issued a 23-page decision Thursday in the suit The Met dropped the Russian soprano from future engagements shortly after Russia invaded Ukraine in February 2022 Met General Manager Peter Gelb had demanded she repudiate Russia President President Vladimir Putin “It is normal for a court to narrow the issues during litigation but this court recognizes that the facts as alleged show that the Met wronged Anna Netrebko and that there is still an important case before it,” Netrebko’s manager “Anna Netrebko remains fully committed to pursuing this complaint to restoring her reputation and to demonstrating that the Metropolitan Opera and Peter Gelb treated her unlawfully.” The case has not yet been scheduled for trial “We’re pleased to see that three of the four claims were dismissed completely and strongly believe that the fourth claim will also prove to be without merit should it go to trial,” the Met said in a statement The American Guild of Musical Artists filed a grievance on Netrebko’s behalf and arbitrator Howard C Edelman ruled in February 2023 that the Met violated the union’s collective bargaining agreement when it canceled deals with Netrebko for three productions Edelman awarded compensation the union calculated at $209,103.48 Netrebko’s lawsuit alleged breach of additional agreements for 40 performances stating those engagements were never finalized into contracts In agreeing to dismiss the defamation claim Torres wrote “Netrebko fails to allege any facts demonstrating that her statements disassociating herself from Putin’s war against Ukraine altered the Met’s subjective belief that she supported the Russian leader.” The judge also wrote the Met’s firing “does not sufficiently implicate her national origin to permit an inference of discrimination.” Torres allowed Netrebko to proceed with claims under the New York State Human Rights Law and New York City Human Rights Law that male counterparts she alleges had connections to Putin and the Russian government were treated more favorably by the Met She cited bass-baritone Evgeny Nikitin and baritones Igor Golovatenko and Alexey Markov Torres wrote the claims were plausible and denied the Met’s motion to dismiss Stay secure and make sure you have the best reading experience possible by upgrading your browser Over the weekend, the Los Angeles Review of Books published a fairly wild essay by Miguel Esteban who, at the tender age of 14, commissioned a now-famous essay on race in science fiction from Octavia Butler. The whole piece is worth a read (the gall of teenage boys the grace of Octavia!) but one detail brought me particular delight: Esteban shares the author bio that Butler provided for the 1979 Fantasy Faire convention is a rather shocking novel of slavery in early America which probably should be read by every white American Having spent too much time agonizing over how straightforward / clever / opaque / forthcoming / fun / boring to be in the various author bios I have been asked to provide over my career, I know how hard writing these can be (and how people will judge you on them) May we all have such clear-eyed confidence and warm And may we all write better author bios in her image [via LARB] Created by Grove Atlantic and Electric Literature Masthead About Sign Up For Our Newsletters How to Pitch Lit Hub Privacy Policy Support Lit Hub - Become A Member Lit Hub has always brought you the best of the book world for free—no paywall you'll keep independent book coverage alive and thriving Metrics details Prices may be subject to local taxes which are calculated during checkout Capturing the interactome of newly transcribed RNA Download references Reprints and permissions Download citation Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Metrics details due to its remarkable ability to differentiate into multiple cell lineages is a valuable model for studying human embryonic development The similarity of the gene expression and chromatin accessibility patterns in these cells to those observed in vivo further underscores its potential as a research tool teratomas derived from human naïve (pre-implantation epiblast-like) pluripotent stem cells (PSCs) have larger embryonic cell diversity and contain extraembryonic lineages making them more suitable to study developmental processes the cell type-specific epigenetic profiles of naïve PSC teratomas have not been yet characterized Using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) we analyzed 66,384 cell profiles from five teratomas derived from human naïve PSCs and their post-implantation epiblast-like (primed) counterparts We observed 17 distinct cell types from both embryonic and extraembryonic lineages resembling the corresponding cell types in human fetal tissues we identified key transcription factors specific to different cell types Our dataset provides a resource for investigating gene regulatory programs in a relevant model of human embryonic development exploring the unique aspects of human development requires suitable models While single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) has been applied to teratomas derived from primed PSCs to study open chromatin a comprehensive study comparing primed and naïve PSCs is still lacking we used scATAC-seq to generate a dataset encompassing 66,384 cell profiles These profiles were obtained from five teratomas of which three derived from human naïve PSCs covering both embryonic and extraembryonic lineages resembling corresponding cell types in human fetal tissues Further analysis pinpointed key transcription factors enriched in cell type-specific accessible regions of chromatin such as SPI1 (transcription factor PU.1) in myeloid cells and TFAP2C (transcription factor AP-2γ) in extraembryonic lineages Our dataset is valuable for dissecting the cis-regulatory logic of embryonic cell fate specification during multilineage differentiation enhancing our understanding of normal human embryonic development and offering insights potentially useful for disease prevention and producing functional cells for therapy All mouse experiments were approved by and conducted in accordance with the guidelines set by the corresponding ethics committees of BGI (license number: BGI-IRB A23019) and the Guangzhou Institutes of Biomedicine and Health (license numbers: IACUC2021002 and GIBH-LMEC2023-004-01 (AL)) Human H9 embryonic stem cells (ESCs) were obtained from WiCell Research Institute Primed human ESCs were routinely cultured in mTeSRTM1 medium (Stemcell Technologies 85850) on plates coated with extracellular matrix (Geltrex (ThermoFisher SH30028.02) and treated with 0.5 mM EDTA (Invitrogen and the cells were passaged as small clumps using a Pasteur pipette (Greiner bio-one Feeder cells derived from ICR mouse embryonic fibroblasts (mitomycin-C treated) were maintained around 24 hours in DMEM (Corning 10-013-CMR) supplemented with 10% FBS (Natocor SFBE) before using them for generating 4CL naïve PSCs primed human H9 ESCs were washed with DPBS then cells were dissociated into single cells with TrypLE (Gibco The resulting single cells were plated at a density of 1,000–1,500 cells/cm2 on feeders in mTeSRTM1 medium supplemented with 10 µM Y-27632 (Axon 1683) and 24 hours later the medium was switched to 4CL medium composed of 1:1 mix of Neurobasal medium (Gibco and cells were passaged as single cells (1:5 to 1:8) every 3–4 days; optionally 5 µM Y-27632 was added in the medium for the first 24 hours after passaging a 200 µl pre-chilled 1:1 mixture of DMEM/F12 and Matrigel was used to suspend 1 million cells Male NOD-SCID IL2Rg−/− mice aged 6–8 weeks were subcutaneously injected with this cell suspension Teratomas were collected approximately 9 weeks post-injection and were directly processed to prepare cell suspensions for scATAC-seq The process involved converting transposed single-nucleus suspensions into barcoded scATAC-seq libraries through several steps: droplet encapsulation The DNA concentration of each library was measured using a Qubit ssDNA Assay kit and sequenced on a DIPSEQ T1 sequencer at the China National GeneBank (CNGB) Arrow file of each library was created using ‘createArrowFiles’ function with ‘filterFrags’ set 50 by reading in accessible read fragments for each library a predicted gene expression matrix based on the accessibility of each gene loci was calculated using ‘addGeneScoreMatrix’ function with default parameter Cell with fewer than 1,200 fragments or a TSS (transcription start site) enrichment lower than 7 were excluded Potential doublets were detected and removed using the ‘filterDoublets’ function with default parameters Uniform Manifold Approximation and Projection (UMAP) embedding was performed based on Iterative Latent Semantic Indexing (LSI) dimensionality which generated using the top 25,000 variable genome tiles Cell clusters were identified using the Shared Nearest Neighbor (SNN) graph based on LSI dimensions Cell types were annotated by manually inspecting the ‘gene activity score’ and accessible regions of canonical marker genes The union of all marker genes for teratoma cell types and fetal organogenesis cell types was used as features for calculating the correlation then peaks were defined using the ‘addReproduciblePeakSet’ function with default parameters cell-type differential peak analysis was performed using the ‘getMarkerFeatures’ function (FDR < 0.05 & Log2 FC > 1) Enriched motifs for each cell type were identified using the ‘peakAnnoEnrichment’ function motif enrichment (-log10 (P value)) greater than 5 were preserved ‘addGroupCoverages’ and ‘getFootprints’ were then used to obtain cell type-specific TF footprints these TF footprints were visualized using the ‘plotFootprints’ function Schematic depicting the key experiments and data analysis (b) Main steps of data processing and analysis Scatter heatmap showing the distributions of the TSS enrichment scores and unique fragments of individual libraries generated from naïve PSC-derived teratomas (a) Violin plot illustrating the distribution of unique fragments (c) and TSS enrichment score (d) for each library (e) Heatmap showing the Pearson correlation among the libraries in this study based on the gene activity score (f) Line plot showing the enrichment of scATAC-seq signals around TSS Biological replicates of teratomas are highlighted by different colors (g) UMAP showing the five corresponding biological replicates of naïve and primed PSC-derived teratomas (h) UMAP highlighting the cells of naïve (left panel) and primed (right panel) PSC-derived teratomas Identification of key regulatory TFs for both embryonic and extraembryonic lineages (a) Heatmap showing the cell type-specific peaks (left panel) and enriched motifs in these differentially accessible regions (right panel) (b) Line plot showing the footprint of representative cell-type specific TFs in scATAC-seq data Our study provides a comprehensive dataset of the cis-regulatory logic of cell fate specification during multilineage differentiation in human PSC-derived teratomas Knowledge resulting from further exploration of this dataset will have broad implications for enhancing our understanding of human embryonic development and the production of functional cells for therapeutic applications Systematic experiments involving more PSC lines and other naïve media will be relevant to ensure the applicability and generalizability of the findings Cao, J. et al. 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Mol Ther 26, 219–237, https://doi.org/10.1016/j.ymthe.2017.09.007 (2018) Download references We thank all our team members for their support and the China National GeneBank (CNGB) for offering the services of sequencing for this project This project was supported by the National Natural Science Foundation of China (32370848 and 32250710149 to M.A.E. the Chinese Academy of Sciences–Japan Society for the Promotion of Science joint research project (GJHZ2093 to M.A.E.) the CAS President’s International Fellowship Initiative (CAS-PIFI) for special experts (2020FSB0002 to M.A.M) and partially supported by Science and Technology Planning Project of Guangdong Province was supported by the China Postdoctoral Science Foundation (Grant No These authors contributed equally: Jinxiu Li Wellcome Trust-Medical Research Council Institute of Metabolic Science Guangzhou Institutes of Biomedicine and Health and Guangzhou Medical University conducted the experiments with help from Y.Li provided relevant advice regarding data interpretation and manuscript preparation provided essential materials and infrastructural support for the single-cell technologies wrote the manuscript with input from all authors and the manuscript was reviewed and approved by all authors Download citation DOI: https://doi.org/10.1038/s41597-024-03558-9 Metrics details The majority of mammalian genomes are devoted to transposable elements (TEs) Whilst TEs are increasingly recognized for their important biological functions they are a potential danger to genomic stability and are carefully regulated by the epigenetic system the full complexity of this regulatory system is not understood we show that TEs are suppressed by heterochromatic marks like H3K9me3 and are also labelled by all major types of chromatin modification in complex patterns including bivalent activatory and repressive marks We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE and Rrp8 caused widespread changes in TE expression and chromatin accessibility with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs Our work reveals the complex patterns of epigenetic regulation of TEs there are at least 1100 distinct types of TE for which the epigenetic regulation is unclear we reveal that TEs are marked by chromatin modifications in complex patterns We find evidence not only of repressive marks but widespread marking of TEs by activatory marks including bivalent marking of TEs by repressive H3K9me3 When we knocked down a panel of chromatin regulators 29 of 41 led to the deregulation of expression of at least one type of TE and Rrp8 led to widespread changes in the expression of TEs and a corresponding change in chromatin accessibility we explore the consequences of these observations by showing that the loss of chromatin modifiers induces a gene expression program similar to totipotent 2 cell (2C) embryos characterized by the upregulation of MERVL TEs and 2C-specific genes our data suggests that the chromatin modifying system manages the expression of TEs by context-specific deposition of chromatin marks that regulate the chromatin state and expression level of TEs A concern in the analysis of repeats is the use of multimapped reads for multimapped reads only the highest scoring alignment was kept To reduce bias due to random distribution of reads across TE copies we considered TEs as metagenes that describe the entire set of TE copies across the genome but it should be kept in mind that the analysis of individual TE copies can be ambiguous indicating broad and complex patterns of chromatin marks on TEs they are marked by both activatory and repressive chromatin marks b Relational network for the chromatin marks (purple) Edges were drawn between a chromatin mark and a TE if the chromatin mark or CM was enriched at least 2-fold Node sizes are proportional to the network degree Selected subgroups are indicated on the network c Read count tag density pileups (In RPKM) of the indicated chromatin marks and CMs for the selected TEs The gray line indicates the input/IgG control d Example genomic views for the indicated TEs Care should be taken in interpreting genomic views due to uncertainty in mapping reads to specific TE copies this applies to all genome views in the manuscript suggesting CTCF binding to L1 is species-specific and these results demonstrate the interconnected binding patterns of the TEs by CMs through chromatin marks although CMs bind promiscuously to TEs in a complex chromatin environment it is unclear if they are directly regulating the expression and chromatin state of these TEs We include Chd4 and Mcrs1 in the analysis below but it should be noted that these two knockdowns are differentiating and interpretation of their effect on TEs is complicated there was little evidence of differentiation This data set provides a system to look at the short-term deregulation of TEs when CMs are lost boxes indicate the upper and lower quartiles and the whiskers indicate 1.5*interquartile range These results suggest that younger TEs are more likely to be under active epigenetic regulation these observations indicate a complex code of CMs regulating sets of TEs by altering chromatin marks These results show that changes in accessibility are a suitable proxy for chromatin changes Loss of CMs opens chromatin at specific TEs. a Heatmap of the fold-changes in chromatin accessibility (measured by ATAC-seq) at TE types. The list of TE types are those that have 20% more or 20% less open or closed chromatin. Selected TE types are indicated, and the full table of all TE chromatin changes is in Supplementary Data 5 b Bar chart of the number of TE types that acquire open chromatin in a unique shRNA knockdown (left) or in more than one shRNA knockdown (right) c Boxplots showing the relationship between chromatin (ATAC-seq The boxplots contain all TE types that acquire open chromatin P values were derived from a Mann–Whitney U test d Boxplots of the levels of ATAC-seq (top rows light gray) for selected TE families for the indicated CM knockdown e Example genome views of individual genomic TEs showing specific chromatin marks The examples show TEs that acquire open chromatin and expression in the indicated shRNA knockdown Examples include the LINE1 elements (L1Md_T f Enrichment of chromatin marks at TE types that become open in response to the indicated shRNA knockdown Significance is derived from a Fisher exact test P < 0.01 and is indicated with a asterisk and the 2C gene expression program remains unclear The x-axis indicates the overall level of expression of the knockdown-specific genes d Upregulation of a 2C-related gene signature by the indicated CM knockdowns A 2C-related gene signature was generated by taking the fold-change of all 2C genes versus ESCs and taking the top 200 fold-change upregulated genes The expression of those top 200 2C genes was then measured in the indicated knockdowns e MA-scatter plots showing the expression of all genes and TEs in the shRnf2 Labels and red spots indicate the expression of the shRNA target gene and selected 2C-related genes (Zscan4a/b/c/d/e/f-cluster Note that the effect is not related to deregulation of Trim28 or Kdm1a These results suggest that there are multiple convergent pathways that can drive cells to a 2C state although whether all of these factors are converging on the same pathway or act independently remains unclear a careful balance is maintained between the potential benefits of TEs and this control is carried out by the epigenetic regulatory system Our data indicate that TEs are marked by many activatory marks We also observed bivalent marking of TE chromatin by H3K9me3 and H3K27ac which may help to explain why we only observed a limited number of downregulated TEs in response to CM knockdown as ESCs express over 200 TE types at levels comparable to many genes Bivalent marking may mean that these TEs are kept in partially activated and repressed states It is increasingly clear that TEs are involved in normal biological processes our study reveals the complexity of epigenetic regulation of TEs in ESCs TEs are marked not only by repressive chromatin marks but are also widely marked by activatory chromatin marks including patterns of simultaneous marking by activatory and repressive marks We show that the loss of CMs caused specific changes in TE expression and chromatin accessibility and these effects are not limited to the formation of heterochromatin or DNA methylation but encompass a large fraction of known chromatin modifications This work suggests that the regulation of TEs is a function of overlapping epigenetic pathways and that a major task of the epigenetic system is to manage the expression of TEs All experiments were performed in mouse E14 ESCs (RRID:CVCL_C320) to avoid any differences in genetic background that may influence the number of TEs Mouse ESCs were grown in serum + LIF medium: DMEM-HIGH GLUCOSE (SH30022.01 1% (v/v) non-essential amino acids (25-025-CI 0.5% (v/v) penicillin-streptomycin solution (SV30010 and the library was then PCR amplified for the appropriate number of cycles Libraries were purified with a Qiaquick PCR (Qiagen) column and were quantified using a KAPA Library Quantification kit (KK4824 Kapa Biosystems) according to the manufacturer’s instructions Library integrity was checked by gel electrophoresis the ATAC library was sequenced on a NextSeq 500 using a NextSeq 500 High Output Kit v2 (150 cycles) (FC-404-2002 Illumina) according to the manufacturer’s instructions Samples that did not closely correlate with other replicate samples or were outliers (R2 correlation < 0.6) A second approach was used to generate a 2C-associated gene signature by taking the top 200 upregulated genes in each CM knockdown and then measuring the fold-change of those genes in the 2C sample Mapping statistics and details of all the samples used in this study are contained in Supplementary Data 1 No statistical methods were used to predetermine sample size, and experiments were not randomized. The investigators were not blinded to the allocation of experiments, nor the outcome. The number of biological replicates are described in the figure legends, or in Supplementary Data 1 Samples were considered statistically significant at P < 0.05 The statistical test used is indicated in the figure legend Further information on experimental design is available in the Nature Research Reporting Summary linked to this article Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire Retrotransposable elements and human disease Exploring the read-write genome: mobile DNA and mammalian adaptation Transposable elements at the center of the crossroads between embryogenesis The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs Regulatory activities of transposable elements: from conflicts to benefits Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication Evolution of the mammalian transcription factor binding repertoire via transposable elements Transposable elements have rewired the core regulatory network of human embryonic stem cells Transcription factor profiling reveals molecular choreography and key regulators of human retrotransposon expression The majority of primate-specific regulatory sequences are derived from transposable elements Transposable element exaptation into regulatory regions is rare Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses Stability and flexibility of epigenetic gene regulation in mammalian development Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos Co-option of endogenous viral sequences for host cell function Retroviral transcriptional regulation and embryonic stem cells: war and peace C2H2 zinc finger proteins greatly expand the human regulatory lexicon Systematic identification of factors for provirus silencing in embryonic stem cells TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells Embryonic stem cell potency fluctuates with endogenous retrovirus activity Evolutionally dynamic L1 regulation in embryonic stem cells HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells Estimating enrichment of repetitive elements from high-throughput sequence data Genome-wide maps of chromatin state in pluripotent and lineage-committed cells Polycomb complexes act redundantly to repress genomic repeats and genes Biotinylation of histones represses transposable elements in human and mouse cells and cell lines and in Drosophila melanogaster Novel histone biotinylation marks are enriched in repeat regions and participate in repression of transcriptionally competent genes Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells Transposable element origins of epigenetic gene regulation Enigma of retrotransposon biology in mammalian early embryos and embryonic stem cells Silencing of endogenous retroviruses: when and why do histone marks predominate An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells An endosiRNA-based repression mechanism counteracts transposon activation during global DNA demethylation in embryonic stem cells KAP1 controls endogenous retroviruses in embryonic stem cells Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo A LINE1-nucleolin partnership regulates early development and ESC identity Transposable element mediated innovation in gene regulatory landscapes of cells: re‐visiting the “gene-battery” model Regulation of mouse retroelement MuERV-L/MERVL expression by REX1 and epigenetic control of stem cell potency A genome-wide screen in EpiSCs identifies Nr5a nuclear receptors as potent inducers of ground state pluripotency Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1 Methylation-dependent and -independent genomic targeting principles of the MBD protein family Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells The Daxx/Atrx complex protects tandem repetitive elements during DNA hypomethylation by promoting H3K9 trimethylation EpiFactors: a comprehensive database of human epigenetic factors and complexes The SIN3A/HDAC corepressor complex functionally cooperates with NANOG to promote pluripotency Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin DNA-binding proteins and nucleosome position Chromatin accessibility dynamics during iPSC reprogramming The landscape of accessible chromatin in mammalian preimplantation embryos Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons Models of global gene expression define major domains of cell type and tissue identity Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells A molecular roadmap for the emergence of early-embryonic-like cells in culture RNA helicase DDX5 inhibits reprogramming to pluripotency by miRNA-based repression of RYBP and its PRC1-dependent and -independent functions RYBP represses endogenous retroviruses and preimplantation- and germ line-specific genes in mouse embryonic stem cells Role of endogenous reverse transcriptase in murine early embryo development Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells MuERV-L is one of the earliest transcribed genes in mouse one-cell embryos A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two‐cell embryos Genomic analysis of LPS-stimulated myeloid cells identifies a common pro-inflammatory response but divergent IL-10 anti-inflammatory responses ATAC-seq: a method for assaying chromatin accessibility genome-wide The octamer is the major form of CENP-A nucleosomes at human centromeres RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets Gene ontology analysis for RNA-seq: accounting for selection bias analyzing and displaying heterogeneous genomic and high-throughput sequencing data deepTools: a flexible platform for exploring deep-sequencing data MEME SUITE: tools for motif discovery and searching Download references This work was supported by the National Natural Science Foundation of China (31801217 the Shenzhen Science and Technology Innovation Committee general program (JCYJ20170307110638890) and the Science and Technology Planning Project of Guangdong Province (2017B030314056) Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL) State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences A*STAR Institute of Molecular and Cell Biology and prepared the manuscript with assistance from M.A.E Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-018-08006-y By | 10/28/2021 12:16 am | Be the First to Comment! HBO Max has announced its first adult animated pickup from the continent The Warnermedia-owned streaming platform has greenlit Poor Devil (Pobre diablo) who would rather be a Broadway star than follow in his father’s footsteps commissioning editor and vp of original programming at HBO Spain We all know people who have had to make a decision whether to join the family business or follow in their parents’ footsteps Poor Devil obviously takes this to the extreme and does so in a very funny way following in the rich tradition of Warnermedia’s adult animations I’m expecting a lot of people are going to instantly fall in love with the Stan and his demonic cat The 8 x 20 min series is created and written by Miguel Esteban with Esteban directing and Helena Pozuelo onboard as co-writer having co-created live-action shows like Netflix’s The Neighbor and Comedy Central’s The End of Comedy Salvat and Antonio Trashorras are executive-producing for HBO Max and Sonia Martínez are the executive producers for Buendía Estudios The animation will be provided by Rokyn Animation Studios in Granada there were 69.4 million HBO Max and HBO subscribers at the end of Q3 2021 and — as of today — six European countries: Spain Variety and C21Media first reported the news of Poor Devil Alex Dudok de Wit is Deputy Editor of Cartoon Brew Two dozen Palm Desert Walmart employees were arrested Wednesday in connection with allegations that, during a two-week period in September, they embezzled money from the store via gift cards according to a news release from the Riverside County Sheriff's Department, received information about an embezzlement scheme at the Walmart 24 suspects are accused of loading money onto Walmart gift cards by using a fraudulent coupon code adding that more than 1,000 unauthorized transactions were made from Sept More: Palm Fire in Desert Hot Springs grows at 40 acres Fifteen were detained at the Riverside County Jail in Indio on suspicion of embezzlement and conspiracy charges: 33-year-old resident of Palm SpringsDaniel Gonzalez 41-year-old resident of Palm DesertMarianne Calizo 21-year-old resident of Palm DesertMaria Zelaya 26-year-old resident of Desert Hot SpringsImauny Marshall 19-year-old resident of Cathedral CityCarol Collins 49-year-old resident of Desert Hot SpringsNoemi Zelaya 29-year-old resident of Desert Hot SpringsMaria Contreras 42-year-old resident of La QuintaAriadna Mayorga 21-year-old resident of Desert Hot SpringsAlicia Herrera 53-year-old resident of Desert Hot SpringsMiguel Esteban 25-year-old resident of Bermuda DunesRoberto Luna 29-year-old resident of La QuintaSelene Melchor-Molina 31-year-old resident of Desert Hot SpringsAmy Vasquez 31-year-old resident of La QuintaEdwin Rios 19-year-old resident of Desert Hot Springs  The investigation also recovered items believed to have been bought by the suspects  using the fraudulent Walmart gift cards More: Police say a man exposed himself to a girl in a Walmart restroom the day after he was convicted of sexual battery By | 03/08/2023 9:23 am | Be the First to Comment! Thanks to early efforts from broadcasters like Fox animated series for adult audiences have been popular in the U.S for decades and producers have been happy to create programming to meet the demand of audiences it has taken far longer for local animated series aimed at adult audiences to catch on That’s not to say that adult animation isn’t a commodity in Spain shows like The Simpsons and Rick and Morty are hugely popular there but the country doesn’t have a tradition of producing animated series for adults That changed recently when HBO Max commissioned its first Spanish original animated series Poor Devil (Pobre Diablo) from creators Miguel Esteban with animation handled by Granada-based studio Rokyn Animation under the creative direction of Manuel Sicilia a young man about to enter adulthood who also happens to be the literal spawn of Satan Stan is left with only one month before he’s supposed to fulfill his destiny by plunging all of humanity into utter chaos Stan is more interested in becoming a Broadway star so he takes a gap month to go live in New York and experience the life of a thespian the series itself will feel immediately recognizable to fans of Spanish film and tv and not just because the characters speak castellano with a Spanish accent “Although the series takes place in New York we didn’t want to write from an American point of view,” Esteban told Cartoon Brew “We wanted to tell the story and make the series that came naturally to us but that could be appreciated by anyone.” the show’s creators needed a long creative leash and and executive producer Miguel Salvat were happy to oblige “We were able to keep it original because of the tremendous freedom given to us by Warner Bros.,” Reyes explained “For the good of our story and our characters I’m so grateful that they put their faith in us and let us make the show we wanted to make.” Reyes designed all the characters himself in a style that he’s fine-tuned over the years there is an incongruity between the malevolence of the characters and their friendly almost stuffed-animal-like designs that is immediately evident I wanted them to have a very friendly look at first that would adapt to the story,” Reyes explained the creators chose to skip any type of realism and draw New York the way they recognized it from tv as that’s how most viewers around the world would recognize the city One major challenge that the crew faced when developing the show was creating half-hour-long episodes The showrunners had experience writing live-action episodes that long but their animation work had previously been relegated to short films of five to six minutes “We never let ourselves think about how long the series needed to be,” Esteban recalled “I would have been scared to think that way and the process would have been too difficult to move forward We came up with a story and characters that were interesting to us the show’s writers melded their live-action writing expertise and animation storyboarding experience applying the visual comedy and codes that they’d learned doing short-form animation to their long-form scripts Although Poor Devil stands out as a Spanish novelty now its creators are hopeful that adult animated series made in Spain will be more common in the future and they know for a fact that artists want to work on it “There aren’t a lot of productions like this in Spain so artists were really excited to work with us,” Reyes explained “It was a good mix of promising younger talent and established professionals who wanted to do something like this in Spain We hope that there will be more projects like this in the country in the near future.” Jamie Lang is the former Editor-in-Chief of Cartoon Brew A big new international classical music festival Riga Jurmala Music Festival was launched in Latvia this year It welcomes world top orchestras such as Bavarian Radio Symphony Orchestra London Symphony Orchestra and conductors like Zubin Mehta The line-up of soloists includes fabulous stars like Yuja Wang Miloš and many young rising stars like Seong-Jin Cho The festival was made possible thanks to a powerful supportive group of investors Mr Aven said at the opening press conference that his goal is to create a significant music festival that would be competitive with similar festivals in Europe Festival’s executive director Miguel Esteban – a co-founder of the Verbier festival Vice President for Artists and Events at the Universal Music live event U-Live – mentioned that the artistic team wants to create something exciting of high quality and that orchestras have reacted already very positively to the new event “It’s a new incredible journey to start!” This new festival will take place in 4 different weekends The opening weekend was held from 23 rd to 25 th of July in the historical Golden Hall of Latvian National Opera and in the Great Guild Hall First orchestra to be presented was the famous Bavarian Radio Symphony Orchestra known as the orchestra of legendary Latvian conductor Mariss Jansons Maestro couldn’t take part in the festival and orchestra played under the baton of Finnish conductor Susanna Mälkki The first soloist during this weekend was Lithuanian-born violinist Julian Rachlin He is the winner of Eurovision Young Musician contest and has already worked with such conductors like Claudio Abbado Another famous soloist was Austrian pianist Rudolf Buchbinder known for his interpretations of the First Viennese School Young rising stars in the line-up were already well-known Lithuanian-Russian pianist Lukas Geniushas and Briton Martin James Bartlett the graduate of the Moscow Conservatory is the second prize winner on such prominent competitions as the International Tchaikovsky Competition in Moscow and the International Chopin Competition in Warsaw legendary piano professor at the Moscow Conservatory 23-years old Martin James Bartlett the winner of BBC Young Musician of the Year 2014 All information about upcoming events is on the website www.riga-jurmala.com Riga Jurmala Music Festival was lucky enough to become for its artistic director very experienced and well-known Martin T:son Engstroem Martin T:son Engstroem got his degree in music history and slavic studies at Stockholm University he was the Vice-President of Deutsche Grammophon for the sector “Artists and Repertoire” from 2003 to 2005 the Senior Executive Producer & Artist Development. He has been a member of the juries in numerous competitions Tchaikovsky Competition and Paganini Competition 1991 he founded one of the world’s most prominent classical music festival in Verbier Engstroem is also a founder of a new big classical music festival in Tsinandali The first edition of Tsinandali Festival takes part from 8 th to 22 nd of September How was it possible to create such a star-studded festival in Latvia Martin T:son Engstroem: In Latvia had developed quite a unique situation Music festivals usually start with limited financial resources and build around what’s available in the area But here we had people who wanted to create a big international classical music festival and supported it in every way offered me the post of festival's artistic director I am quite busy with my current festivals and hadn’t planned to lead another festival I have been always passionate about classical music Sweden and Finland were the few places where great Soviet artists could regularly perform I met all these legendary musicians and made many contacts At that time there were Jurmala and Sochi Goskontsert’s official summer resorts Emil Gilels spent their summers in Jurmala My honeymoon with my first wife was in Jurmala Riga reminds me of Stockholm's old town I felt some kind of nostalgia and thought – now I can give to this region something back Petr Aven asked me for a concept of the festival and suggested to focus on orchestras There are not too many orchestra-oriented festivals around My idea is to bring same orchestras to the festival for at least three consecutive years the audience can get emotional connection with the performers It is important that orchestras and artists become part of the festival and are not like vagabonds who come and go Riga Jurmala Music Festival invited now four orchestras: Bavarian Radio Symphony Orchestra Russian National Orchestra with its founder conductor and pianist Mikhail Pletnev; Israeli Philharmonic Orchestra with Zubin Mehta and the London Symphony Orchestra with Gianandrea Noseda who was originally planned to perform with the Bavarian Radio Symphony Orchestra had serious health problems and we had to find a replacement – wonderful Susanna Mälkki My other big goal is to bring tourists to the area introduce and promote the land with the festival music travel is becoming more and more popular it is the French who buy most of tickets to the Salzburg Festival While doing this you can rely on your experience from the Verbier festival but organizing a festival is a never-ending work In earlier times already artist’s poster somewhere on streets gained attention and the concert was sold out you must think hard about how to reach your audience I always tell my team: the audience is not buying tickets the concert For that you need to know what people want We do research and try to find a way to the listeners it seems that you already know your audience But we start from scratch every year and have to be very creative you cannot sit down and say: now everything works by itself People are buying more and more tickets at the last minute Or take the courage and hope that the concerts will still be sold at a bargain price I don't know the audience here so well Are they conservative or curious or want to listen to something new for example Messiaen’s Turangalîla Symphony Your festivals have always star-studded cast But how do you find and select new young artists there I am curious about everything: where the talent comes from why one builds up a career and another one doesn't I often find interesting young people when I am sat in a jury of competition I am often in the jury of the Tchaikovsky Competition This year I was chairman of the jury for the violinists If I hear someone there whom I like – it doesn't have to be the first prize it may be as well the 4th or 5th prize – then I invite them to my festival And then I'll try to support them the way I can Do you plan to invite more artists from the Baltic countries to the festival in the future This year we were very much looking forward to receiving maestro Jansons for our festival but he's a very busy conductor with two big orchestras I am also interested in some Latvian young instrumentalists there are some very interesting pianists in Latvia we are also interested in other famous musicians from the Baltic States But my primary desire right now is to bring world stars to the area How to become a successful artist nowadays Being successful right now is very different from how it was in earlier times Nowadays a musician must be a communicator The audience is not an abstract set of people artist must know how to interact with its audience the artist has to convince his audience what he is doing He may not be the greatest musician of our time Big record companies – like Deutsche Grammophon – prefer artists who communicate well give interesting interviews and look good on photos What should be done to popularize classical music We are living in times where people have very little patience and lack of concentration it’s hard for them to sit still for a longer period I see that the audience for classical music is growing and I believe that classical music will survive all his problems If there is no interest in classical music at home it is difficult for young people to find their way to it Many discover the classical music in their adult years You might not start by visiting all concerts during the season you don't have to be afraid of doing something wrong I've told to my kids: imagine living in a five-room apartment where one room is classical music You won't open the doors to these rooms This also means that your living space has become very small But do give yourself a chance and your space will become more and more open A subscription to The Baltic Times is a cost-effective way of staying in touch with the latest Baltic news and views enabling you full access from anywhere with an Internet connection. Subscribe Now! 2025 © The Baltic Times /Cookies Policy Privacy Policy were celebrating an aunt’s birthday at their maternal grandmother’s house on July 10 and slept there that night a group of hooded and armed police officers showed up and arrested the brothers just for lifting the white-and-blue Nicaraguan flag on the streets and all of Jinotepe hasn’t been the same since they were kidnapped by government forces Lesage is a housekeeper and her husband is a carpenter They lived with their three sons: Luis Miguel Esteban “I don’t know how to live without them,” Lesage said The dark side of Nicaragua The Esteban brothers are being held at the Granada Penitentiary They were beaten badly when they were taken to the station,” Lesage said The three brothers are university students Jean Carlos studies business administration They’re university students,” their mother said “People can vouch for them because everyone knows them.” She says their only crime was going out onto the streets with a blue-and-white flag their mother said Luis had been shot in the arm when paramilitary groups attacked the city they composed some songs against Ortega’s regime Luis and Jean sing reggaetón under the stage names of Místico and Janco I dream about them asking me for food,” Lesage said “This is something I don’t wish on any mother I don’t know if they’re eating or drinking The brothers will have their first hearing on Aug The only thing she wants is to have he sons back home 23,000 Nicaraguans seek asylum in Costa Rica: UN Read the original story in Spanish at La Prensa This story was translated into English and republished in The Tico Times as part of a partnership with La Prensa to help bring their coverage of the Nicaraguan crisis to an English-speaking audience the Met's General Manager Peter Gelb discussed soprano Anna Netrebko and why she and the Met have parted ways Netrebko's General Manager responds here to certain statements in the article In an online story called Peter Gelb on the ins and outs of the Met’s new cinema season Limelight spoke to the General Manager of New York’s Metropolitan Opera about the new Met in HD season opening in Australia cinemas on 19 November Peter Gelb spoke about Russian soprano Anna Netrebko who was originally scheduled to perform in François Girard’s production of Lohengrin and why Netrebko and the Met have parted ways has requested a right of response to certain statements that appear in the article “Regarding the quote by the subject of the article ‘I think she would have had a great success [laughs]’: An employer fires an employee The Metropolitan Opera could not have fired Anna Netrebko since the agreements between them include the clause ‘It is specifically agreed and understood that nothing contained in this agreement shall constitute The Met the employer of Singer or Singer its employee.’ On the other hand,.. Get unlimited digital access from $4 per month Subscribe Contribute to Limelight and support independent arts journalism The centenary of Puccini's death gives creatives the chance to reflect on what makes his operas so special and explore new ways to stage them The American mezzo-soprano is making her Australian debut in Mahler 3 with Melbourne Symphony Orchestra She just wishes she could have brought her dog Ahead of his performances for Opera Australia the world’s number one tenor Jonas Kaufmann talks about his highly anticipated role debut and upcoming season Is it justifiable to ban Russian music and musicians following Russia’s invasion of Ukraine Should art rise above international conflicts Roger Neill traces the extraordinary history of St Kilda's Simonsen family and gives us a taste of their fascinating life This month’s performance highlights from ABC Classic its co-star Renée Fleming speaks to Limelight about the making of the opera and why it is "crucial" to stage new work The editors of Limelight share their selection of the most exciting classical music The Met's General Manager on season details new music that does "the shocking thing of pleasing audiences" and the Netrebko dilemma Check out our playlists from our latest issue Our free Weekly Newsletter delivers the latest arts news reviews and features to your inbox each Saturday From the minds that gave life to the hilarious Capítulo 0 an ordinary kid except for the small fact that he is the Antichrist he has one month left for ‘the prophecy‘ to be fulfilled and carry out his mission: plunge humanity into horror and chaos But this poor devil is only interested in one thing: singing and dancing in a Broadway musical the series is directed by Esteban himself and animated by the Granada studio Rockyn Animation Reyes plays Stan and Sevilla takes on the role of Mephisto in addition to being Stan’s godfather The voice cast is completed by Ignatius Farray as Satan; Gakian as Samael -a demoness specialized in possessions- creative duo and fundamental pillars in the creation of programs such as Muchachada Nui or Museo Coconut are part of the birth of what we know as ‘the new model of humor’ in Spain with La hora chanante a series to which Serielizados Fest will pay tribute on the occasion of its 20th anniversary  “We all know people who have had to make the decision to join the family business or follow in their parents’ footsteps,” comments Miguel Salvat “‘Pbre Diablo,’ takes this to the extreme and does it in a very funny and original way following the rich tradition of WarnerMedia’s adult animations.” The collaborator hasn't left anyone indifferent with her revelation | España Diario PEOPLE Surprise at What Belén Esteban Has Revealed LiveSan Blas's resident has revealed to her colleagues and the audience of 'Ni que fuerámos' the step she has taken03/03/2025 18:50:00h by María Merino known for her frankness in sharing details of her personal life She did so with an unexpected revelation live on the show Ni que fuéramos The wife of Miguel Marcos has announced that she has decided to join the world of fitness all to get in shape and look better than ever she has once again showcased that sincerity She did so by surprising everyone with a crucial step: she has decided to get in shape During the live broadcast, the collaborator of Ni que fuéramos enthusiastically shared her new routine "Today I started with the bike and treadmill but because of my leg." A statement that surprised both her studio colleagues and the audience No one expected her to now reveal her sporty side David Valldeperas suggested the possibility of hiring a personal trainer for her on the show This statement demonstrates the seriousness with which she is taking this new life stage trusting professionals to guide her on her path to a healthier life She is clear that she wants to do things right and not joke around on a set Belén Esteban is taking her entry into sports very seriously | Canal QuickieBelén's decision to start an exercise routine at the gym is an inspiring example for many people who postpone taking care of their physical health Her story shows that it's never too late to start and that it's possible to adopt healthy habits that improve quality of life   NEW ON FACEBOOK! 📲 Click here to receive the hottest royal and celebrity news directly to your Facebook, for FREE and EXCLUSIVE! Don't miss out! her transparency in sharing both the positive aspects and the challenges of this process offers a realistic view of what it means to introduce significant changes into the daily routine This honesty is undoubtedly one of the reasons why Belén continues to be a beloved and respected figure in the Spanish television landscape Lydia Lozano is going through one of the most delicate moments of her life after the passing of her mother The collaborator attended to reporters shortly after learning the sad news helped her a lot at a very specific moment in her life it was when her brother was diagnosed with coronavirus that the ambulance driver offered his help to the panelist Lydia Lozano has highlighted what Miguel did for her during a delicate moment in her life | Canal QuickieAn event that Lydia now recalled by acknowledging that she had received condolences from Miguel Marcos helped Lydia Lozano's brother during the pandemic | Europa Press"My guardian angel," this is how Lydia defined her colleague's husband in 2021 during the time her brother fought against the mentioned disease Words that now make perfect sense when listening to the collaborator's emotional account The fact that the television personality has mentioned Belén Esteban's husband highlights the close bond existing between her and Lydia Lozano Those who were once enemies now keep an intimate friendship that has been revealed Lydia Lozano's Comment Confirms That the Enmity Between Her and Belén Is a Thing of the Past | MediasetProof of this was also the presence of Andrea Janeiro's mother at the Madrid funeral home in Tres Cantos More for the bad many times," explained Jesulín de Ubrique's ex to the reporters It was last Wednesday when the passing of Sol Hernández, Lydia Lozano's mother at 95 years old, was announced. A sad news that caught the journalist in Barcelona, a city she had visited for the Sant Jordi festival The panelist had traveled to the Catalan capital to sign books as it was also Book Day Information that left the collaborator in shock as she did not expect this circumstance to occur suddenly shared details of the news through a social media post passed away last Wednesday at 95 years old | Instagram @lydialozanoof"Today my heart and affection are with Lydia Lozano my dear friend and colleague," wrote the paparazzi on his Instagram profile "Last night we were in Barcelona," he continued implying that he had reunited with Lozano after some time Words after which the journalist revealed the sad news