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

Abstract

Originally two types of Polycomb Repressive Complexes (PRCs) were described, canonical PRC1 (cPRC1) and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s). Both cPRC1s and ncPRC1s contain Ring finger protein (RING1, RNF2) and Polycomb group ring finger catalytic (PCGF) core, but in ncPRCs, RING and YY1 binding protein (RYBP), or YY1 associated factor 2 (YAF2), replaces the Chromobox (CBX) and Polyhomeotic (PHC) subunits found in cPRC1s. Additionally, ncPRC1 subunits can associate with versatile accessory proteins, which determine their functional specificity. Homozygous null mutations of the ncPRC members in mice are often lethal or cause infertility, which underlines their essential functions in mammalian development. In this review, we summarize the mouse knockout phenotypes of subunits of the six major ncPRCs. We highlight several aspects of their discovery from fly to mice and emerging role in target recognition, embryogenesis and cell-fate decision making. We gathered data from stem cell mediated in vitro differentiation assays and genetically engineered mouse models. Accumulating evidence suggests that ncPRC1s play profound role in mammalian embryogenesis by regulating gene expression during lineage specification of pluripotent stem cells.

Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription

“…These complexes are subdivided, based on the Polycomb group ring finger (PCGF) subunits they contain. Different PCGFs all bind to the central RING1-RYBP catalytic core in a mutually exclusive way [83] and often have tissue-specific and molecular functions [99] (reviewed in [100]). Six PCGF paralog proteins were purified in the different ncPRC1 complexes, hence, there are six different ncPRC1 subtypes described and numbered after the PCGF subunit they contain.…”

“…The direct regulatory targets of different PCGFs also differ profoundly [99]. Knowing that, it is not surprising that knockout phenotypes of the mutations induced in the genes coding for subunits of the alternative PRC1-type complexes also highly vary (reviewed in [100]). Alternative ncPRC1 complexes are characterized with high target specificity and have few compensatory functions.…”

RYBP is important for cardiac progenitor cell development and sarcomere formation

“…The precise mechanism by which RYBP exerts its functions throughout development is still not thoroughly known. The activity of RYBP containing ncPRC1 complexes is strongly influenced by their subunit composition and stoichiometry [9,37]. ncPRC1s contain RING finger protein 1 (RING1 also known as RING1A), RNF2, Polycomb Group Ring Fingers (PCGFs) and RYBP or YY1 associated factor 2 (YAF2) as the core subunits instead of Chromobox (CBX) and Histone phosphorylation (HPH) subunits of PRC1s.…”

“…It is possible that RYBP could either act via polycomb dependent or polycomb independent manner, regulating key lineage determinant factors which are critical for progenitor formation in wild type conditions. Moreover, RYBP can perform more than one function being a moonlighting protein, and member of several multiprotein complexes besides ncPRC1s [9,37]. This brings up the possibility that RYBP can also function as a part of other multimeric protein complexes other than ncPRC1s and regulate cardiac progenitor as well as sarcomere formation consequently (Fig 7).…”

“…RYBP is an epigenetic regulator and a core member of the non-canonical Polycomb Repressive Complex 1 types (ncPRC1s). Originally ncPRC1s were identified as repressor complexes, but later studies have proven that they can contribute to gene activation as well [ 8 , 9 ]. In vivo studies have demonstrated that RYBP is essential for the early mouse embryonic development and the development of organ systems such as the central nervous system, hematopoietic system and the eye [ 10 – 12 ].…”