CpG island erosion, polycomb occupancy and sequence motif enrichment at bivalent promoters in mammalian embryonic stem cells

Abstract

In embryonic stem (ES) cells, developmental regulators have a characteristic bivalent chromatin signature marked by simultaneous presence of both activation (H3K4me3) and repression (H3K27me3) signals and are thought to be in a ‘poised’ state for subsequent activation or silencing during differentiation. We collected eleven pairs (H3K4me3 and H3K27me3) of ChIP sequencing datasets in human ES cells and eight pairs in murine ES cells, and predicted high-confidence (HC) bivalent promoters. Over 85% of H3K27me3 marked promoters were bivalent in human and mouse ES cells. We found that (i) HC bivalent promoters were enriched for developmental factors and were highly likely to be differentially expressed upon transcription factor perturbation; (ii) murine HC bivalent promoters were occupied by both polycomb repressive component classes (PRC1 and PRC2) and grouped into four distinct clusters with different biological functions; (iii) HC bivalent and active promoters were CpG rich while H3K27me3-only promoters lacked CpG islands. Binding enrichment of distinct sets of regulators distinguished bivalent from active promoters. Moreover, a ‘TCCCC’ sequence motif was specifically enriched in bivalent promoters. Finally, this analysis will serve as a resource for future studies to further understand transcriptional regulation during embryonic development.

Targeting the epigenome in malignant pleural mesothelioma

“…Although often associated with promoter hypermethylation, polycomb-mediated gene silencing may occur independent of DNA methylation (86,87), typically in the context of bivalent chromatin, exhibiting occupancy of PcG proteins and simultaneous activation (H3K4Me3) and repressive (H3K27Me3) histone marks. Frequently observed in stem cells, bivalent chromatin maintains differentiation-related genes in a repressed, but poised state for rapid activation or permanent silencing depending on the differentiation signal (88,89 (90). Collectively, these experiments were the first demonstration that EZH2 is over-expressed in MPM, and that PRC-2 is a potential therapeutic target in these neoplasms.…”

Causal gene regulatory network inference using enhancer activity as a causal anchor

“…This enrichment was much stronger than for the ChIP bound targets of Cbx7 (p < 10 −5 ). Cbx7 is a part of the PRC complex, which binds predominantly at bivalent chromatin at promoters of transcription regulators in ES cells (Mantsoki et al, 2015).…”

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

“…Computational analysis of the dataset from different ChIP-seq experiments also showed that genome-wide locations of PRC1 and PRC2 complexes can be successfully predicted with the use of mapping locations sizes of CpG islands in parallel with different activator motifs. The main conclusion was that large CpG islands depleted of activating motifs are bound by both PRC complexes in pluripotent stem cells [204,207]. In more recent studies bivalent domains were connected to different nucleosome remodeling complexes too (reviewed in [211]).…”

“…These bivalent markings suggest that certain genes are poised for both activation and repression in stem cells [204,207]. Serine 2 phosphorylation of RNA polymerase II is present in the coding regions of the active genes, but it is absent from paused and poised complexes.…”

“…It seems that the presence of PRC1 complex can block RNA polymerase II at the elongation phase [210]. The promoter regions of overwhelming majority of key developmental genes are bound to both PRC1 PRC2 and efficiently retain the H3K27 mark during differentiation and remain stably repressed [204,207]. Computational analysis of the dataset from different ChIP-seq experiments also showed that genome-wide locations of PRC1 and PRC2 complexes can be successfully predicted with the use of mapping locations sizes of CpG islands in parallel with different activator motifs.…”