Abstract
Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.
Highlights
Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII)
Our genome-wide analyses of RNAPII and Polycomb occupancy in mouse ESCs (mESCs) identified two major groups of PRC targets: (1) repressed genes associated with PRCs and unproductive RNAPII and (2) expressed genes bound by PRCs and active RNAPII5
We focus on active PRC-target genes that are marked by PRCs (H3K27me[3] modification or both H3K27me[3] and H2Aub1) and active RNAPII (S5pS7pS2p), and compare these with “active” genes
Summary
Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). Embryonic stem cells (ESCs) are capable of self-renewing and differentiating into all somatic cell types[1, 2], and their homeostasis is maintained by epigenetic regulators[3] In this context, Polycomb repressive complexes (PRCs) are important histone modifiers, which play a fundamental role in maintaining the pluripotent state of ESCs by silencing important developmental regulators[4]. Our genome-wide analyses of RNAPII and Polycomb occupancy in mESCs identified two major groups of PRC targets: (1) repressed genes associated with PRCs and unproductive RNAPII (phosphorylated at S5 but lacking S2p; PRC-repressed) and (2) expressed genes bound by PRCs and active RNAPII (both S5p and S2p; PRC-active)[5] Both types of genes are marked by H3K4me[3] and H3K27me[3], a state termed bivalency[1, 10]. This pattern of two distinct chromatin states could imply a digital switch between actively transcribing and repressed promoters within a population of cells, thereby introducing more cell-to-cell variation in gene expression compared to genes with both alleles in active chromatin states
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