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Essential and unexpected role of YY1 to promote mesodermal cardiac differentiation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE35370 | GEO | 2013/06/01

SECONDARY ACCESSION(S): PRJNA152599

REPOSITORIES: GEO

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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

Gene expression profiles in in vitro cardiogenesis.

Project description:We performed time-dependent, genome-wide analysis to explore gene expression profiles during in vitro cardiogenesis from embryonic stem cells to cardiac progenitor cells. Total RNA was extracted from undifferentiated stem cells, early mesodermal cells, cardiac mesodermal cells and cardiac progenitor cells. As a result of cluster analysis, Cited gene family was considered as candidate genes in cardiogenesis. Cited4 gene expression was specific for early cardiogenesis and Cited4 functioned as a cell cycle controling factor for early cardiac progenitor cells. Embryoid body was formed as in vitro cardiogenesis. Total RNA was extracted from Rex1-positive undifferentiated stem cells at day 0, Bra-positive early mesodermal cells at day 4.5, Flk1-positive cardiac mesodermal cells at day 4.5 and Nkx2.5-positive cardiac progenitor cells at day 7.5.

2016-03-31 | E-GEOD-63069 | biostudies-arrayexpress

Cardiac differentiation of embryonic stem cells recapitulates embryonic cardiac development.

Project description:Mouse embryonic stem cells can differentiate in vitro into spontaneously contracting cardiomyocytes. The main objective of this study was to investigate cardiogenesis in cultures of differentiating embryonic stem cells (ESCs) and to determine how closely it mimics in vivo cardiac development. We identified and isolated a population of cardiac progenitor cells (CPCs) through the use of a reporter DNA construct that allowed the expression of a selectable marker under the control of the Nkx2.5 enhancer. We proceeded to characterize these CPCs by examining their capacity to differentiate into cardiomyocytes and to proliferate. We then performed a large-scale temporal microarray expression analysis in order to identify genes that are uniquely upregulated or downregulated in the CPC population. We determined that the transcriptional profile of the mESC derived CPCs was consistent with pathways known to be active during embryonic cardiac development. We conclude that in vitro differentiation of mESCs recapitulates the early steps of mouse cardiac development. Keywords: embryonic stem cell, differentiation, cardiac progenitor, cardiogenesis

2007-08-30 | GSE5671 | GEO

Chromatin accessibility profiles 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 | GSE210638 | GEO

Transcriptional specification of early cardiac precursor cells at single cell resolution

2023-04-07 | GSE208153 | GEO

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

2023-04-07 | GSE210639 | GEO

Transcription profiling of hearts from Nkx2.5 knockout mice (mouse model of congenital heart disease) at embryonic day 12.5 shows Nkx2.5 is not only crucial during early steps of cardiogenesis but also plays an important role at later developmental stages

Project description:The NK2 family of homeobox genes constitutes a family of transcription factors that play an important role in different developmental processes. Members of this group are characterized by two highly conserved protein domains: the homeodomain, conferring DNA binding activity, and the NK2-specific domain (NK2-SD) of yet unknown function. One of the best characterized members of this group is the early cardiogenic marker Nkx2.5. Loss of function of Nkx2.5 leads to embryonic lethality around E10.5 due to an arrest of heart development at the looping stage. We have further dissected the function of Nkx2.5 in vivo by creating a knockout mouse line harboring an in frame deletion of the NK2-SD by Cre/loxP mediated excision. Homozygous mutant mice die at E14.5 due to severe cardiac malformations, e.g. common AV canal, DORV, and VSD. Lack of the NK2-SD leads to downregulation of the ventricular markers MLC-2v and Irx4 specifically in the right ventricle, and is accompanied with reduced right ventricular function. This function of Nkx2.5 seems to be independent of its ability to bind target DNA, since lack of the NK2-SD does not alter the DNA binding activity of Csx/Nkx2.5 in vitro. Heterozygous mutant mice show a spectrum of cardiac defects related to cardiac septation and valve morphogenesis, but lack conduction system defects as reported for heterozygous Nkx2.5 mice. The phenotype observed in NK2-SD mutant mice shows that Nkx2.5 is not only crucial during early steps of cardiogenesis but also plays an important role at later developmental stages. Embryos were isolated at embryonic day 12.5. The entire embryo heart was taken and isolated in ice-cold PBS and immediately frozen on dry-ice. Total RNA was extracted from pooled samples of wildtype, heterozygous and mutant embryos.

2007-12-13 | E-GEOD-528 | biostudies-arrayexpress

Braveheart is a long non-coding RNA necessary for cardiac lineage commitment

Project description:Purpose: Long non-coding RNAs (lncRNAs) display development-specific gene expression patterns, yet we know little about their precise roles in lineage commitment. Here, we discover a novel mammalian heart-associated lncRNA, AK143260, necessary for cardiac lineage specification. Methods: Gene expression profiles of mouse ESCs and differentiated organs were analyzed for master regulators of lineage commitment. The AK143260 transcript was shown to be strongly expressed in mESCs and in cells undergoing cardiac differentiation. Its role in cardiac differentiation was examined using depletion and in vitro differentiation systems, with morphological and gene expression profiling at different time-points. Results: mESCs depleted of AK143260, named Braveheart, fail to differentiate into cardiomyocytes and to activate a core cardiac gene regulatory network including key transcription factors driving cardiogenesis. We show that Braveheart functions upstream of MesP1 (mesoderm posterior 1), a transcription factor critical for specification of the earliest known multi-potent cardiovascular progenitor and in promoting epithelial-mesenchymal transition (EMT). Consistent with this, Braveheart depletion leads to morphological defects and loss of cardiogenic potential in a defined in vitro cardiomyocyte differentiation system. Furthermore, Braveheart is necessary to maintain myocardial gene expression and myofibril organization in neonatal cardiomyocytes. Conclusions: These findings reveal that Braveheart is an important regulator of cardiac commitment and implicate lncRNAs as potential therapeutic targets for cardiac disease and regeneration. Gene expression profiles from control and Bravheart-depleted mESCs were obtained by RNA-Seq on an Illumina HiSeq2000 instruments at Days 0,3,6 and 9. Gene expression profiles from mESCs, MEFs, partially reprogrammed MEFs and miPS cells were obtained by RNA-Seq on Illumina GAII/GAIIx instruments.

2013-01-30 | E-GEOD-39656 | biostudies-arrayexpress

Scl specifies hemogenic endothelium and inhibits cardiogenesis via primed enhancers [ChIP-seq]

Project description:Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates. ChIP-seq with Scl, Hand1, Lsd1, Ezh2, H3K4me1 and H3K27ac in different cell types with mesodermal origin. Scl ChIP-seq in WT, SclKO, SclKO-iScl and Gata12KO mES cell derived day4 EB (embryoid body) Flk1+ mesodermal cells, SclKO-iScl ES cells and MEL cells; Hand1 ChIP-seq in WT mES cell derived day4 EB Flk1+ mesodermal cells; Lsd1 and Ezh2 ChIP-seq in WT and SclKO mES cell derived day4 EB Flk1+ mesodermal cells. ChIP-seq of histone modifications H3K4me1 and H3K27ac in WT, SclKO and Gata12KO mES cell derived day4 EB Flk1+ mesodermal cells, HPC7 hematopoietic progenitor cells and HL1 cardiomyogenic cells

2015-01-01 | E-GEOD-47082 | biostudies-arrayexpress

Gene expression profiles in in vitro cardiogenesis.

2016-03-31 | GSE63069 | GEO

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