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Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the 'histone code' concept and interrogate it at the nucleosome level., Competing Interests: MM, JB, IP, AV, NH, EW, MM, RW, ZG, HT, LM, UO, SH, KN, EM, KK, MC, MC, ZS, BV Affiliated with EpiCypher Inc; the author has no financial interests to declare, HF, CM No competing interests declared, MK A board member of EpiCypher Inc; the author has no financial interests to declare, (© 2024, Marunde, Fuchs et al.)

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 a 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 resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation., Competing Interests: KJ, FJ, KP, SC, BT, GF, KN, NY No competing interests declared, MM, JB, SG, IP, NH, AV, SH, HT, LM, UO, EP, EW, MC, MM, MC, ZS is affiliated with EpiCypher, Inc The author has no financial interests to declare, ZG, KR is affiliated with EpiCypher, Inc. The author has no financial interests to declare, KK owns options in EpiCypher, Inc, MC owns stock/serves on the Consultant Advisory Board for Kathera Bioscience Inc and holds266 US patents (8,133,690; 8,715,678; and 10,392,423) for compounds/methods for inhibiting267 SET1/MLL family complexes, MK is a BOD member of EpiCypher Inc, BS is a co-founder and BOD member of EpiCypher, Inc, (© 2023, Jain et al.)