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Chromatin accessibility profiles of early cardiac precursor cells at single cell resolution

ABSTRACT: Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE210638 | GEO | 2023/04/07

REPOSITORIES: GEO

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Transcriptional specification of early cardiac precursor cells at single cell resolution

Project description:Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.

2023-04-07 | GSE208153 | GEO

A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors

2023-04-07 | GSE210639 | GEO

A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

Project description:The regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle, or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/β-Catenin signaling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated β-Catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and β-Catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs prior to their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involve unanticipated functions of β-Catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs. YFP+ cells marking precardiac mesoderm (Isl1-cre domain) were FACS-sorted (w/wo stabilized Beta-catenin). Their total RNA was amplified with the WT-Ovation Pico RNA Amplification System, fragmented and labeled with the FL-Ovation cDNA Biotin Module V2 (Nugen). The hybridization, staining and scanning of the Affymetrix GeneChips were performed in the Gladstone Genomics Core Lab. Raw data generated from at least three independent experiments were further analyzed by the group of Dr. Ru-Fang Yeh at the Center for Informatics and Molecular Biostatistics, UCSF.

2009-05-13 | E-GEOD-15232 | biostudies-arrayexpress

Early lineage restriction and regional segregation during mammalian heart development

Project description:Cardiac development arises from two sources of mesoderm progenitors, the first (FHF) and the second heart field (SHF). Mesp1 has been proposed to mark the most primitive multipotent cardiac progenitors common for both heart fields. Here, using clonal analysis of the earliest prospective cardiovascular progenitors in a temporally controlled manner during the early gastrulation, we found that Mesp1 progenitors consist of two temporally distinct pools of progenitors restricted to either the FHF or the SHF. FHF progenitors were unipotent, while SHF progenitors, were either uni- or bipotent. Microarray and single cell RT-PCR analysis of Mesp1 progenitors revealed the existence of molecularly distinct populations of Mesp1 progenitors, consistent with their lineage and regional contribution. Altogether, these results provide evidence that heart development arises from distinct populations of unipotent and bipotent cardiac progenitors that independently express Mesp1 at different time points during their specification, revealing that the regional segregation and lineage restriction of cardiac progenitors occurs very early during gastrulation. We used microarrays to characterize the molecular mechanisms that control Mesp1 progenitor specification and lineage segregation during the early stage of cardiac mesoderm formation, 50 Mesp1 H2B-GFP+ or Mesp1 H2B-GFP- cells at E6.5 or E7.5 from mouse embryos were sorted for RNA extraction, amplification and hybridization on Affimetrix microarrays. Microaarrays were performed on Mouse Genome 430 PM strip Affymetrix array. The overall design was repeated in two different biological samples.

2014-07-10 | E-GEOD-59033 | biostudies-arrayexpress

JAK Activity Regulates Mesoderm Cell Fate and Cardiac Differentiation by controlling MESP1 expression

Project description:Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent molecule that can significantly increase MESP1 expression. CYT387 was also found to enhance cardiomyocyte differentiation from hPSCs in vitro. Mechanistical studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesoderm cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development.

2024-03-31 | GSE262452 | GEO

Early lineage restriction and regional segregation during mammalian heart development

2014-07-10 | GSE59033 | GEO

Essential and unexpected role of YY1 to promote mesodermal cardiac differentiation

Project description:Rationale: Cardiogenesis is regulated by a complex interplay between transcription factors and chromatin-modifying enzymes. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor-binding site analysis on upstream promoter regions of genes that are enriched in ES cell-derived CPCs. From 32 candidate transcription factors screened, we found that YY1, a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1 kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays and in vivo chromatin immunoprecipitation (ChIP) and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with GATA4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by ES cell-based assays where we show that the over-expression of YY1 enhanced the cardiogenic differentiation ES cells into CPCs in a cell autonomous manner. Conclusion: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. We report the identification of putative YY1 target genes in cardiac progenitor cells (CPCs). Two samples of independently FACS-purified eGFP+ CPCs were examined against the input.

2013-06-01 | E-GEOD-35370 | biostudies-arrayexpress

A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

2009-05-13 | GSE15232 | GEO

Gene expression analysis of hESC-derived-MESP1 expressing progenitors

Project description:A hESC MESP1-MCHERRY reporter line was used to isolate and study the molecular character of MESP1 expressing pre-cardiac progenitors, derived from hESC. MESP1 is a key-transcription factor for pre-cardiac mesoderm and is marking the progenitor for almost all cells of the heart. This reporter line was used to study cardiac differentiation and the derivation of early cardiac progenitors in vitro. hESCs were differentiated towards the cardiac lineage, expressing MESP1-mCherry at day 3 of differentiation. Total RNA obtained from isolated MESP1-mCherry expressing progenitors was compared to that of non-MESP1-expressing progenitors and undifferentiated hESCs in order to characterize MESP1-specific transcription factors and proteins.

2014-09-01 | E-GEOD-56721 | biostudies-arrayexpress

Matrix-dependent cardiac progenitor cell fate is instructed by the early regulation of YAP and Plk2

Project description:Although recent studies support regenerative potential based on cardiac progenitor cells (CPCs), it remains unclear what cues regulate CPC fate. Using 2- and 3D-culture models, we demonstrate that the two most abundantly expressed matrix proteins in the heart, laminin and fibronectin, have opposite roles in CPC fate decision. CPCs on fibronectin showed predominantly nuclear localization of the transcriptional co-activator YAP and maintained proliferation. In contrast, seeding on laminin induced cytosolic retention and degradation of YAP and altered gene expression, which preceded decreased proliferation and enhanced lineage commitment. RNA-sequencing identified Plk2 as candidate target gene of YAP. Plk2 expression depended on YAP stability, was rapidly downregulated on laminin, and its regulation was sufficient to rescue and/or mimic the CPC response to laminin and fibronectin, respectively. These findings propose a novel role of Plk2 and identify an early molecular mechanism in matrix-instructed CPC fate with potential implications for therapeutic cardiac regeneration.

2017-10-26 | GSE77231 | GEO

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