An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability

Abstract

In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The DNA-bound state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (K9ac, K14ac, K18ac) is linked to increased engagement of H3K4me3 by the BPTF PHD finger, but it is unknown if this mechanism has broader extension. Here we show that cis H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and further extends to H3K4 writers, notably methyltransferase MLL1. This regulation is nucleosome-dependent and also observed in vivo, where H3 acetylation correlates with increased levels of cis H3K4me. These observations reveal an acetylation "chromatin switch" on the H3 N-terminal tail that modulates the accessibility and function of H3K4 methylation in chromatin. Our findings also resolve the long-standing question of why H3K4me3 levels are linked with H3 acetylation.

Competing Interest Statement

EpiCypher is a commercial developer and supplier of reagents (e.g. PTM-defined semi-synthetic nucleosomes; dNucs and versaNucs) and platforms (dCypher) used in this study.