Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains

TLDR

Bivalent chromatin domains marked by H3K27me3 and H3K4me3 are found at promoters of more than 2,000 genes in embryonic stem cells. The study aimed to map PRC1 and PRC2 occupancy and key histone marks across the genome in human and mouse ES cells to understand bivalent domain structure and function. The authors performed genome‑wide ChIP‑seq for PRC1, PRC2, and histone marks in human and mouse ES cells and used computational genomics to identify sequence determinants of Polycomb binding. Bivalent domains segregate into two classes: PRC1‑positive domains that retain H3K27me3 upon differentiation, are highly conserved, and enriched at developmental regulator promoters, and PRC2‑only domains; CpG island size, location, and motif content largely predict PRC1 and PRC2 occupancy, indicating that large CpG islands lacking activating motifs recruit full Polycomb complexes to establish epigenetic memory.

Abstract

In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes—the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.