Bivalent chromatin protects reversibly repressed genes from irreversible silencing

Bivalent chromatin is characterized by the simultaneous presence of H3K4me3 and H3K27me3, histone modifications generally associated with transcriptionally active and repressed chromatin, respectively. Prevalent in embryonic stem cells, bivalency is postulated to poise lineage-controlling developmental genes for rapid activation during embryogenesis while maintaining a transcriptionally repressed state in the absence of activation cues, but its function in development and disease remains a mystery. Here we show that bivalency does not poise genes for rapid activation but protects reversibly repressed genes from irreversible silencing. We find that H3K4me3 at bivalent gene promoters--a product of the underlying DNA sequence--persists in nearly all cell types irrespective of gene expression and confers protection from de novo DNA methylation. Accordingly, loss of H3K4me3 at bivalent promoters is strongly associated with aberrant hypermethylation and irreversible silencing in adult human cancers. Bivalency may thus represent a distinct regulatory mechanism for maintaining epigenetic plasticity. HIGHLIGHTSO_LIBivalent chromatin does not poise genes for rapid activation C_LIO_LIH3K4me3 at bivalent promoters is not instructive for transcription activation C_LIO_LIH3K4me3 at bivalent promoters protects reversibly repressed genes from de novo DNA methylation C_LIO_LILoss of H3K4me3/bivalency is associated with aberrant DNA hypermethylation in cancer C_LI