RYBP and Cbx7 Define Specific Biological Functions of Polycomb Complexes in Mouse Embryonic Stem Cells

Abstract

The Polycomb repressive complex 1 (PRC1) is required for decisions of stem cell fate. In mouse embryonic stem cells (ESCs), two major variations of PRC1 complex, defined by the mutually exclusive presence of Cbx7 or RYBP, have been identified. Here, we show that although the genomic localization of the Cbx7- and RYBP-containing PRC1 complexes overlaps in certain genes, it can also be mutually exclusive. At the molecular level, Cbx7 is necessary for recruitment of Ring1B to chromatin, whereas RYBP enhances the PRC1 enzymatic activity. Genes occupied by RYBP show lower levels of Ring1B and H2AK119ub and are consequently more highly transcribed than those bound by Cbx7. At the functional level, we show that genes occupied by RYBP are primarily involved in the regulation of metabolism and cell-cycle progression, whereas those bound by Cbx7 predominantly control early-lineage commitment of ESCs. Altogether, our results indicate that different PRC1 subtypes establish a complex pattern of gene regulation that regulates common and nonoverlapping aspects of ESC pluripotency and differentiation.

BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase

“…For example, non-canonical PRC1 ligases could have an expanded list of client substrates and if so, it might explain why they have not maintained optimal binding to the nucleosome surface. The requirement for non-canonical PRC1 complexes in ES cell proliferation 62 , retroviral repression 63 , and regulation of metabolic genes and cell cycle progression 25 may be consistent with a need for greater flexibility (faster intrinsic rate, lower affinity for substrate) compared with the action of canonical PRC1 during development (where precision may be of paramount importance). The recent rapid progress in this area suggests that important elements of PCGF-RING1 E3 ligase function and regulation may yet be discovered.…”

“…Recently, it has been appreciated through work in many labs that, in addition to canonical PRC1, several variant PRC1 complexes are present in mammalian cells [18][19][20][21][22][23][24][25][26][27][28][29] . These are defined by the PCGF family member present 23 , and the copurifying subunits also differ by complex subtype 22,23,25 . Opinions currently differ on which type of complex, canonical 25 or non-canonical 23,29 , may contribute more strongly to H2A K119 ubiquitination.…”

“…These are defined by the PCGF family member present 23 , and the copurifying subunits also differ by complex subtype 22,23,25 . Opinions currently differ on which type of complex, canonical 25 or non-canonical 23,29 , may contribute more strongly to H2A K119 ubiquitination. However, very little data have been published comparing directly the two classes of ligases.…”

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

“…Inactivation of Rnf2 resulted in premature neural differentiation of embryonic neural stem cells (NSCs) in conditional Rnf2 mouse mutant [232], the same mouse line that Calés et al used [227]. Further ES cell studies revealed that RNF2 target genes repress Wnt signaling [223]. One of the latest in vitro studies showed that knockdown of Rnf2 promotes cell-cycle arrest and apoptosis in prostate cancer cells [233] and gastric cancer cells [234].…”

“…Genes regulated by RYBP containing complexes rarely completely silenced, often highly transcribed, and primarily involved in the regulation of metabolism and cell cycle progression. CBX7 containing complexes are typically found on promoters of completely silenced genes, which are involved in early lineage commitment of ES cells [223]. The binding site of CBX7-and RYBP-containing PRC1 complexes overlaps in certain genes, but on other targets their binding are mutually exclusive.…”