Acquired Tissue-Specific Promoter Bivalency Is a Basis for PRC2 Necessity in Adult Cells

• Distinct groups of promoters in adult tissues carry both H3K4me3 and H3K27me3 marks
• Tissue-specific H3K27me3 appears late in development and keeps genes silent
• Many other genes with stable or dynamic H3K27me3 are unaffected by loss of this mark
• Bivalent genes are derepressed in PRC2 null cells in proportion to H3K4me3 levels

SummaryBivalent promoters in embryonic stem cells (ESCs) carry methylation marks on two lysine residues, K4 and K27, in histone3 (H3). K4me2/3 is generally considered to promote transcription, and Polycomb Repressive Complex 2 (PRC2) places K27me3, which is erased at lineage-restricted genes when ESCs differentiate in culture. Molecular defects in various PRC2 null adult tissues lack a unifying explanation. We found that epigenomes in adult mouse intestine and other self-renewing tissues show fewer and distinct bivalent promoters compared to ESCs. Groups of tissue-specific genes that carry bivalent marks are repressed, despite the presence of promoter H3K4me2/3. These are the predominant genes de-repressed in PRC2-deficient adult cells, where aberrant expression is proportional to the H3K4me2/3 levels observed at their promoters in wild-type cells. Thus, in adult animals, PRC2 specifically represses genes with acquired, tissue-restricted promoter bivalency. These findings provide new insights into specificity in chromatin-based gene regulation.

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