Essential and Unexpected Role of YY1 to Promote Mesodermal Cardiac Differentiation
1Massachusetts General Hospital, Massachusetts, UNITED STATES. Circulation Research
(Impact Factor: 11.02).
03/2013; 112(6). DOI: 10.1161/CIRCRESAHA.113.259259
Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs).
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 embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (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, in vivo chromatin immunoprecipitation, 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 embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.
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.
Available from: Jun Wang
- "YY1 is also important for the early cardiac differentiation . For example, using Mesp1-cre, which is activated at E6.5 (Brand, 2003), to ablate YY1 in mesoderm during embryogenesis resulted in the loss of cardiac precursor cells and early embryonic lethality (Gregoire et al., 2013), and the gain-of-function study also showed that overexpressing YY1 in embryonic stem cells promoted cardiogenic differentiation (Gregoire et al., 2013). More recently, we used two cre lines to inactivate YY1 during mouse cardiogenesis. "
Available from: ILimbek Beketaev
- "YY1 is also important for the early cardiac differentiation. For example, using Mesp1-cre, which is activated at E6.5 (Brand, 2003), to ablate YY1 in mesoderm during embryogenesis resulted in the loss of cardiac precursor cells and early embryonic lethality (Gregoire et al., 2013), and the gain-of-function study also showed that overexpressing YY1 in embryonic stem cells promoted cardiogenic differentiation (Gregoire et al., 2013). More recently, we used two cre lines to inactivate YY1 during mouse cardiogenesis. "
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Mesp1 is critical for early cardiomyocyte differentiation and heart development. We previously observed a downregulation of Mesp1 expression in YY1-ablated embryonic hearts. However, how Mesp1 expression is mediated by YY1 is not well understood.
We excised YY1 in the murine embryos using Sox2-cre, and found that Mesp1 was downregulated in the E7.5 mutant embryos. Also, YY1 activated the 6 kb Mesp1 regulatory element fused to a luciferase reporter. We identified two putative YY1 binding sites in the proximal promoter region of Mesp1 gene, and found that mutation of these sites significantly reduced YY1-induced activation of the Mesp1 promoter. We also uncovered one cognitive site for SP1, one of the earliest binding partners of YY1 identified. Mutation of this SP1 site repressed SP1-induced activation of the Mesp1 promoter. Moreover, YY1 and SP1 synergistically activated the Mesp1 promoter. Consistently, while Lacz expression driven by the wild type 6 kb regulatory element of Mesp1 gene was robust in E7.5 mouse embryos, the mutation of these binding sites in the context of this 6 kb sequence substantially reduced the LacZ expression during embryogenesis.
YY1 and SP1 independently and cooperatively govern the Mesp1 expression during embryogenesis. This article is protected by copyright. All rights reserved.
Available from: PubMed Central
- "YY1 is crucial for embryonic development because homozygous mutation of the yy1 gene in mice results in peri-implantation lethality (18). YY1 is implicated in lineage differentiation of skeletal and cardiac muscle, and in cell growth control (13, 17, 19–24), as well as disease pathways such as dystrophic muscle disease (25–27). YY1 and its target genes are also believed to be central regulators of germinal center B cell development (28), and YY1 has been suggested to regulate genomic targeting of activation induced cytidine deaminase (AID) (29). "
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ABSTRACT: During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Igκ loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation.
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