CRAMP1 drives linker histone expression to enable Polycomb repression

Abstract

In contrast to the well-understood role of core histones in DNA packaging, the function of the linker histone (H1) remains enigmatic. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for H1 in Polycomb repressive complex 2 (PRC2) function. A CRISPR-Cas9 genetic screen using a fluorescent PRC2 reporter identified an essential role for the poorly characterized gene CRAMP1 in PRC2-mediated repression. CRAMP1 localizes to the promoters of expressed H1 genes and positively regulates their transcription. CRAMP1 ablation simultaneously depletes all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, we find that linker histones preferentially localize to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, these data demonstrate a prominent role for linker histones in epigenetic repression by PRC2. • A genome-wide CRISPR screen reveals CRAMP1 is required for PRC2 repression • CRAMP1 binds linker histone genes and drives their expression • Linker histones are enriched at H3K27me3-marked genomic loci • Linker histone insufficiency following CRAMP1 ablation abrogates PRC2 repression Challenging the prevailing view that H1 linker histones represent a general feature of repressed chromatin, Matthews et al. show a specific requirement for H1 in epigenetic repression by PRC2. Ablation of the H1 activator CRAMP1 results in linker histone insufficiency and derepression of PRC2 target genes.