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

In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation ( e.g. , K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has broader extension. Here we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo , H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation ‘chromatin switch’ on the H3 tail that modulates read-write accessibility in nucleosomes and resolve the long-standing question of why H3K4me3 levels are coupled with H3 acetylation. ### Competing Interest Statement MSC owns stock in and serves on the Consultant Advisory Board for Kathera Bioscience Inc. and holds US patents (8,133,690; 8,715,678; and 10,392,423) for compounds/methods for inhibiting SET1/MLL family complexes. EpiCypher is a commercial developer and supplier of reagents (e.g., PTM-defined semi-synthetic nucleosomes; dNucsTM and versaNucs) and platforms (e.g., dCypher) used in this study. MCK and BDS are board members of EpiCypher. KK owns EpiCypher options.