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Unravelling the chromatin landscape and enhancer logic mediating spatiotemporal patterning of early cardiovascular progenitors [ATAC-seq]

ABSTRACT: The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CP remains unknown. Here, by combining ChIP-seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the temporal remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We found that Mesp1 acts as a pioneer transcription factor (TF) and identified Zic TFs as essential cofactors that regulate Mesp1 pioneer activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development.

ORGANISM(S): Mus musculus

PROVIDER: GSE165101 | GEO | 2022/05/18

REPOSITORIES: GEO

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Project description:Mouse heart development arises fromMesp1 expressing cardiovascular progenitors that are specified at the early stage of gastrulation. Lineage tracing and clonal analysisof Mesp1 progenitors revealed that heart development arises from distinct populations of Mesp1+ cardiovascular progenitors (CPs) expressing Mesp1 at different time points during gastrulation that contribute to different heart regions and different cardiovascular lineages. However, it remains unclear what are the molecular mechanisms that control the early regional and lineage segregation of Mesp1 CPs. Here, we performedsingle cell RNA-sequencing of FACS isolated Mesp1 CPs in WT and Mesp1 null embryos at different times to define the cellular and molecular heterogeneity of the Mesp1CPs, identify the role of Mesp1 in regulating cellular heterogeneity and uncover the mechanisms associated with lineage and regional segregation during the early stages of gastrulation.We showed that Mesp1 CPs isolated at E6.75 and E7.25 are molecularly distinct and make the continuum betweenepiblast and later mesodermal cells including hematopoietic progenitors. Single cell transcriptome of Mesp1 deficient CPsshowed that Mesp1 is required for the exitof thepluripotent state and the induction of the cardiovascular gene expression program in vivo.Using dimensional reduction analysis, we identified distinct populations of Mesp1 CPs that correspond to progenitors committed to different celllineages and regions of the heart, identifying the molecular features associated with the early lineage and regional segregation. Notch1CREER lineage tracing, a marker preferentially expressed by one of the different Mesp1CP subpopulations, during the early stage of gastrulation marked almost exclusively ECs, demonstrating theexistence of an early Mesp1 subpopulation committed to the EC fate.This study uncoversthe cellular and molecular heterogeneity associated with early lineage restriction and regional segregation of the heart at the early stage of gastrulation.

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Unravelling the chromatin landscape and enhancer logic mediating spatiotemporal patterning of early cardiovascular progenitors [ATAC-seq]

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