Extraembryonic gut endoderm cells undergo programmed cell death during development (WGBS)
Ontology highlight
ABSTRACT: Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
Project description:Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
Project description:Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
Project description:Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
Project description:Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if these cells persist into later development. Here, we developed a two-color lineage tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of their original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighboring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild type gut while they persist and differentiate further in p53 mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
Project description:To investigate the epigenetic landscape at the interface between mother and fetus, we provide a comprehensive analysis of parent of origin bias in the placenta. Using F1 interspecies hybrids, we sequenced RNA from 23 individual midgestation placentas, five late stage placentas, and two yolk sac samples and then used SNPs to determine whether transcripts were preferentially generated from the maternal or paternal allele. In the placenta, we find 103 genes that show significant and reproducible parent-of-origin bias, of which 78 are novel candidates. Most (96%) show a strong maternal bias which, using multiple models, we demonstrate is not due to maternal decidual contamination. Analysis of the X chromosome also reveals paternal expression of Xist and several genes that escape inactivation, most significantly Rps4x, Fhl1, and Slc38a5. Finally, sequencing individual placentas allowed us to reveal notable expression similarity between littermates. In all, we observe a striking preference for maternal transcription in the midgestation mouse placenta and a dynamic imprinting landscape in extraembryonic tissues, reflecting the complex nature of epigenetic pathways in the placenta. 3'-end Sequencing for Expression Quantification (3SEQ) and SNP Analysis to observe parent-of-origin bias in 28 placental samples at two time points and 2 yolk sac samples
Project description:DNA and Histone-3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb Repressive Complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extraembryonic lineages display non-canonical, globally intermediate DNA methylation levels that includes disruption of local Polycomb domains. To better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse Trophoblast Stem Cells (TSCs). We find that the extraembryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extraembryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.
Project description:To comprehensively delineate the ontogeny of an organ system, we generated 112,217 single- cell transcriptomes representing all endoderm populations within the mouse embryo until midgestation. We employed graph-based approaches to model differentiating cells for spatio- temporal characterization of developmental trajectories. Our analysis reveals the detailed architecture of the emergence of the first (primitive or extra-embryonic) endodermal population and pluripotent epiblast. We uncover an unappreciated relationship between descendants of these lineages, before the onset of gastrulation, suggesting that mixing of extra-embryonic and embryonic endoderm cells occurs more than once during mammalian development. We map the trajectories of endoderm cells as they acquire embryonic versus extra-embryonic fates, and their spatial convergence within the gut endoderm; revealing them to be globally similar but retaining aspects of their lineage history. We observe the regionalized localization of cells along the forming gut tube, reflecting their extra-embryonic or embryonic origin, and their coordinate patterning into organ-specific territories along the anterior-posterior axis.
Project description:To comprehensively delineate the ontogeny of an organ system, we generated 112,217 single- cell transcriptomes representing all endoderm populations within the mouse embryo until midgestation. We employed graph-based approaches to model differentiating cells for spatio- temporal characterization of developmental trajectories. Our analysis reveals the detailed architecture of the emergence of the first (primitive or extra-embryonic) endodermal population and pluripotent epiblast. We uncover an unappreciated relationship between descendants of these lineages, before the onset of gastrulation, suggesting that mixing of extra-embryonic and embryonic endoderm cells occurs more than once during mammalian development. We map the trajectories of endoderm cells as they acquire embryonic versus extra-embryonic fates, and their spatial convergence within the gut endoderm; revealing them to be globally similar but retaining aspects of their lineage history. We observe the regionalized localization of cells along the forming gut tube, reflecting their extra-embryonic or embryonic origin, and their coordinate patterning into organ-specific territories along the anterior-posterior axis.
Project description:DNA and Histone-3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb Repressive Complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extraembryonic lineages display non-canonical, globally intermediate DNA methylation levels that includes disruption of local Polycomb domains. To better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse Trophoblast Stem Cells (TSCs). We find that the extraembryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extraembryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation. Dataset 1: EED co-immunoprecipitation of wild type mouse trophoblast stem cells (TSCs) and Eed knockout TSCs as control, with 3 biological replicates per condition.
Project description:We described a new culture system that can expand the developmental potential of pluripotent stem cells to contribute efficiently to extraembryonic lineage development. To compare the epigenetic landscape of expanded potential stem cells (EPSCs) and standard embryonic stem cells, we performed ChIP-seq study on multiple histone modifications to establish the epigenetic landscape of EPSCs.