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.
FörderungenFondo Europeo de Desarrollo Regional Helmholtz Gemeinschaft National Science Foundation Department of Energy, Basic Energy Sciences Division of Materials Science and Engineering, through the Midwest Integrated Center for Computational Materials (MICCoM) National Science Foundation Graduate Research Fellowship Blood Cancer United Specialized Center of Research NIH/National Institute of General Medical Sciences Swiss National Science Foundation EPFL European Regional Development Fund Fundacion Ramon Areces BioExcel-3: Centre of Excellence for Computational Biomolecular Research Spanish Ministry of Science Deutsche Forschungsgemeinschaft (DFG)