Pcgf5 Contributes to PRC1 (Polycomb Repressive Complex 1) in Developing Cardiac Cells
Polycomb-group (PcG) proteins maintain transcriptional silencing through specific histone modification and are essential for cell-fate transition and proper development of embryonic and adult stem cells. Recent advances in molecular analysis of PcG proteins have revealed that the distinct subunit composition of PRC1 confers specific and nonoverlapping functions for regulation of embryonic and adult stem cells. Here, we provide an overview of recent findings regarding the role of PcG proteins in cardiac development, with focus on the diversity of PcG complexes.
KeywordsPolycomb-group protein Cardiac development Transcriptional silencing Histone modification
Cardiac development is a complex and ordered process that requires cellular specification, proliferation, and differentiation, as well as further migration of cell populations from diverse sites. The primary heart field (PHF) originates in the anterior splanchnic mesoderm, then gives rise first to the cardiac crescent, later to the linear heart tube, and ultimately contributes to parts of the left ventricular (LV) region. The second cardiogenic region, known as the second heart field (SHF), lies in the anterior, posterior, and dorsal to the linear heart tube and is derived from the pharyngeal mesoderm located medial and anterior to the cardiac crescent. Cells from the SHF are added to the developing heart tube and give rise to the outflow tract (OFT), right ventricular (RV) region, and main parts of atrial tissues .
Congenital heart defects (CHDs) represent the most common anomaly seen in human newborns, with a prevalence of approximately 1 % of all births . Traditionally, focus on causes of CHD has involved transcriptional networks during cardiogenesis, because correct alignment and septation of cardiac structures regulated by cardiac specific transcriptional factors, such as Tbx1 , Tbx5 , Tbx20, Gata4, and Nkx2-5 , are essential for cardiac morphogenesis . In addition to these multiple genetic factors, recent studies have shown that some chromatin remodeling factors moderate gene expression to control cardiogenesis and are also involved in the molecular pathogenesis of CHD [2, 3, 4, 5, 6, 7].
43.2 PcG Functions in Cardiac Development
In this review, we primarily focused on the functions of PcG proteins in cardiac development. Their roles have been elucidated via generation of knockout (KO) mice for each of the PcG components. Among the PRC2 components, loss of Suz12, Ezh2, or Eed results in embryonic lethality during the early postimplantation stage [12, 13, 14]. To address the role of PRC2 in cardiac development, Ezh2 and Eed were conditionally inactivated in specified cardiac cells using Nkx2-5:Cre or TnT:Cre [3, 4]. Inactivation of Ezh2 by Nkx2-5:Cre (Ezh2NK) and Eed by TnT:Cre (EedTnT) led to embryonic lethality and several cardiac defects including compact myocardial hypoplasia, whereas inactivation of Ezh2 by TnT:Cre (Ezh2TnT) did not result in severe defects in cardiogenesis despite a modest upregulation of some cardiac genes, probably because of the redundant functions of Ezh1 and Ezh2.
Embryos deficient of Ring1b, a core component of PRC1, also displayed early embryonic lethality caused by gastrulation arrest . Although early developmental arrest in Ring1b KO embryos was partially restored by inactivation of Cdkn2a (Ink4a/ARF), cardiac tissue did not develop in double-KO embryos. Unlike early developmental defects seen in KO mice lacking some of the core PRC1 and PRC2 components, deficiency of other components has been shown to give rise to restricted effects. For example, loss of Rae28/Phc1 resulted in perinatal lethality with cardiac anomalies, double outlet right ventricle, and tetralogy of Fallot [6, 7]. In addition to cardiac defects, Rae28/Phc1 deficient mice also showed craniofacial developmental defects, as well as thymus and parathyroid gland defects as seen in human DiGeorge syndrome.
Among Cbx proteins, Cbx4 may play an important role in cardiogenesis. SUMO-specific protease 2 (SENP2) was reported to regulate transcription of Gata4 and Gata6 , mainly through alteration of the occupancy of Cbx4 on their promoters . In SENP2-deficient embryos, sumoylated Cbx4 accumulates on the promoters of target genes, leading to transcriptional repression of Gata4 and Gata6. Furthermore, Cbx4 mutant mice displayed postnatal lethality with severe hypoplasia of the developing thymus as a result of reduced thymocyte proliferation. However, the function of Cbx4 in cardiogenesis has not been clearly elucidated . Thus, PcG proteins are essential for molecular regulation of the expression of several cardiac genes during embryogenesis and important for cardiac morphogenesis.
43.3 Diversity of PcG Proteins
43.4 Pcgf5 Expression in the Developing Heart
This work was supported by a JSPS KAKENHI Grant (24591595).
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