PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes

Abstract

The ring finger protein PCGF6 (polycomb group ring finger 6) interacts with RING1A/B and E2F6 associated factors to form a non-canonical PRC1 (polycomb repressive complex 1) known as PCGF6-PRC1. Here, we demonstrate that PCGF6-PRC1 plays a role in repressing a subset of PRC1 target genes by recruiting RING1B and mediating downstream mono-ubiquitination of histone H2A. PCGF6-PRC1 bound loci are highly enriched for promoters of germ cell-related genes in mouse embryonic stem cells (ESCs). Conditional ablation of Pcgf6 in ESCs leads to robust de-repression of such germ cell-related genes, in turn affecting cell growth and viability. We also find a role for PCGF6 in pre- and peri-implantation mouse embryonic development. We further show that a heterodimer of the transcription factors MAX and MGA recruits PCGF6 to target loci. PCGF6 thus links sequence specific target recognition by the MAX/MGA complex to PRC1-dependent transcriptional silencing of germ cell-specific genes in pluripotent stem cells.DOI: http://dx.doi.org/10.7554/eLife.21064.001

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].…”

“…Only ncPRC1.6 complex provides link to heterochromatin control system, with its HP1 homolog subunits CBX1 and CBX3. In germ cell differentiation and meiosis regulation ncPRC1.6 has a specific role [173,181,182].…”

“…The ncPRC1.6 complex does not harbor KDM2B or FBX10 subunits. The target genes of ncPRC1.1 and ncPRC1.6 are highly different [173]. It seems PRC1.6 complex is mainly targeted by its DNA binding subunits.…”

“…MAX/MGA heterodimers can independently associate with both PCGF6 and L3MBT2 subunits and target the PRC1.6 complex. The H3K9 specific methyltransferase subunits of the complex, in turn, repress germ cell specific genes in ES cells [173].…”

Histone H2A Monoubiquitination in Neurodevelopmental Disorders

“…Both genotypes were born at less than Mendelian ratio, demonstrated perinatal lethality with the null animals proportionally smaller than control littermates [73, 75]. Besides skeletal transformations, Asxl1 −/− mice exhibit microphthalmia, craniofacial dysmorphisms and myelodysplasia but have not been described as microcephalic [33, 75–77]. Asxl2 −/− mice showed enlarged hearts with interstitial fibrosis and cardiomyocyte disarray and do not exhibit macrocephaly [73, 78].…”