Critical role of YY1 in cardiac morphogenesis

Abstract

Background: Yin Yang 1 (YY1), the only DNA binding polycomb group protein, was reported to regulate cardiomyocyte differentiation during early cardiac mesoderm development. However, whether it contributes to cardiac morphogenesis at later developmental stage(s) during embryogenesis is unknown. Results: We excised YY1 in murine hearts during embryogenesis using two temporal-spatially controlled cre activation approaches, and revealed critical roles of YY1 in cardiac structural formation. Alpha-myosin heavy chain-cre (a-MHC-cre)-mediated cardiomyocyte-specific ablation of YY1 (MHC-YY1) resulted in perinatal death of mutant mice, and Nkx2.5-cre-mediated YY1 null embryos (Nkx2.5-YY1) died embryonically. In the Nkx2.5-YY1 mutants, the endocardial cushions (ECs) of both atrioventricular canal (AVC) and outflow tract (OFT) were hypoplastic due to decreased proliferation and increased apoptosis. Endothelial-to-mesenchymal transition (EMT) progress was also compromised in ECs. Nkx2.5-YY1 mutant hearts had normal formation of extracellular matrix, suggesting that the impaired EMT resulted from the direct loss of YY1. We further uncovered that a number of factors that are involved in normal cardiogenesis were downstream targets of YY1. Conclusions: YY1 plays a critical role in cardiac development and occupies a high-level position within the hierarchy of the cardiac transcriptional network that governs normal cardiogenesis. Developmental Dynamics 244:669-680, 2015. V C 2015 Wiley Periodicals, Inc.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

“…Recent studies showed binding of YY1 to the promoters of highly expressed ribosomal proteins and the nuclear encoded mitochondrial membrane, enzymes, and ribosomal proteins (35) and highlighted the importance of YY1 in cardiomyocyte differentiation and heart morphogenesis (30,31). Notably, cardiacspecific ablation of Yy1 causes severe abnormalities in the heart, indicating that YY2 in the heart does not compensate for YY1 deletion (31). Comparison of YY2 and YY1 ChIP-Seq data ( Fig.…”

“…Recent studies showing that YY1 directly regulates Nkx2.5 expression and promotes cardiogenesis uncovered a novel function for YY1 in cardiomyocyte differentiation and cardiac morphogenesis (30,31). To examine the effect of YY2 on mESC differentiation toward cardiovascular lineages, EBs derived from dox-YY2 mESCs were exposed to doxycycline.…”

cis‐regulatory control of Mesp1 expression by YY1 and SP1 during mouse embryogenesis

“…In our previous work, we identified several YY1 downstream targets, and Mesp1 was one of them and was the most significantly affected (Beketaev et al, ). In the present study, we aimed to further understand how the Mesp1 expression is mediated by working on the cis‐regulatory sequences of Mesp1 gene that was fused to different reporters.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…Many PcG null mutations of one of the orthologs in mice can survive to later embryonic stages; some of them are even viable, showing very mild phenotypes [94] (see Tables 2-5). Furthermore, analyzing the mouse phenotypes of late lethal PcG mutations, it became obvious that although these factors play profound role in homeotic regulation [158,159], their epigenetic repressor functions are also important in hematopoiesis [160][161][162][163] (reviewed in [164] and [165]), neuronal [154,166] (reviewed in [167]) cardiac [168][169][170] and skeletal muscle differentiation [171], as well as in the maintenance of germ cell fate [172][173][174][175].…”

“…Mesp1-cre mediated knockout of Yy1 (Mesp1-YY1) at early developmental stage (at E6.5) resulted in abolished cardiac lineage formation and YY1 together with GATA4 transcriptionally activates early cardiac enhancer, Nkx2.5 [263]. A latest study found that MHC-cre mediated Yy1 null mice (MHC-YY1) displayed congenital heart defects with defective cardiomyocyte proliferation and increased apoptosis, while Nkx2.5-cre mediated Yy1 null mouse embryos (Nkx2.5-YY1) showed hypoplastic endocardial cushions in atrioventricular canal and outflow tract and died around E13.5 [170]. They also identified downstream targets of YY1 that are cardiac morphogenesis regulators (Mesp1, Cited1, eHAND and Dll) [170].…”