Abstract
Polycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis. How Polycomb group (PcG) proteins orchestrate down-regulation of target genes upon differentiation, however, remains elusive. Here, by differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role for the PCGF1-containing variant PRC1 complex (PCGF1-PRC1) to mediate differentiation-associated down-regulation of a group of genes. Upon differentiation cues, transcription is down-regulated at these genes, in association with PCGF1-PRC1-mediated deposition of histone H2AK119 mono-ubiquitination (H2AK119ub1) and PRC2 recruitment. In the absence of PCGF1-PRC1, both H2AK119ub1 deposition and PRC2 recruitment are disrupted, leading to aberrant expression of target genes. PCGF1-PRC1 is, therefore, required for initiation and consolidation of PcG-mediated gene repression during differentiation.
Highlights
Polycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis
To identify the genes that are down-regulated during embryonic stem cells (ESCs)-toEB differentiation in a PRC1-dependent manner, we established Pcgf[1] conditional ESCs from Pcgf1:fl/flRosa26CreERT2tg/+ blastocysts[19,20]
We found that SUZ12 and PCGF2 progressively accumulated at Klf[4], Tbx[3], and Pdgfa after the 8-h stage of ESC-to-embryoid bodies (EBs) differentiation, in a similar fashion to RING1B (Supplementary Fig. 2j)
Summary
Polycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis. By differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role for the PCGF1-containing variant PRC1 complex (PCGF1-PRC1) to mediate differentiationassociated down-regulation of a group of genes. Such structural variety indicates a division of labor among PRC1 and PRC2 complexes, though they share a common function to mediate H2AK119ub[1] or H3K27me[3], respectively This complexity likely confers robustness and reversibility to PcG-mediated gene silencing[10,12,13]. Given that the PCGF1-PRC1 complex can drive de novo formation of Polycomb chromatin domains containing PRC1, H2AK119ub[1], PRC2, H3K27me[3], and canonical PCGF2/4-PRC1, it is plausible that the same complex plays a dynamic role to initiate PcG-mediated silencing[14]. Whether and how PcG factors, PCGF1-PRC1 and other PRC1 sub-complexes, regulate dynamic changes of target gene expression during differentiation remains largely unknown. PCGF1-PRC1 is, required for initiation and consolidation of PcGmediated gene repression during differentiation
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