{"doi":"10.1016/j.molcel.2025.11.030","title":"H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations","abstract":"Histone modifications play crucial roles in genome function. However, how chromatin integrates physiological and metabolic responses at the molecular level remains largely unknown. Acetylation of histone H4 lysine 16 (H4K16ac) is unique, as it directly regulates chromatin architecture. Here, we investigated the roles of two additional H4K16 short-chain acylations, propionylation (H4K16pr) and butyrylation (H4K16bu), in chromatin architecture and transcriptional regulation. We demonstrate distinct in vitro effects of H4K16 acylations on chromatin structure, including inter- and intra-nucleosomal interactions. Utilizing a mouse model of the metabolic disease propionic acidemia, we reveal a transcriptional response concomitant with changes in H4K16 acylations in vivo . Our work suggests the importance of simultaneous action of histone acylations for transcriptional robustness through effects on nucleosomal interactions. We propose that this mode of action distinguishes H4K16 acylations from other modifications that also differ by one carbon, such as methylations. • H4K16 short-chain acylations alter inter- and intra-nucleosomal interactions in vitro • In vivo , H4K16 acylations co-occur and scale with gene expression • Concerted action of acylations during transcriptional responses to metabolic stress Nitsch et al. show that short-chain acylations of histone H4K16, acetylation (C2), propionylation (C3), and butyrylation (C4) modulate chromatin structure in vitro . These effects can translate in vivo into balanced transcription responses under metabolic stress. This study provides insights into how different H4K16 acylations modulate chromatin structure and function.","journal":"Molecular Cell","year":2025,"id":522457,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1189033,"name":"A. E. 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