H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations
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.
Authors
- Modesto Orozco (ORCID: https://orcid.org/0000-0002-8608-3278)
- Shannon Lauberth
- Natalie Möritz
- Shixin Liu (ORCID: https://orcid.org/0000-0003-4238-7066)
- Harsh Nagpal
- Yiheng Wu (ORCID: https://orcid.org/0009-0001-0524-7251)
- Beat Fierz (ORCID: https://orcid.org/0000-0002-2991-3044)
- Gabriella N. L. Chua (ORCID: https://orcid.org/0000-0002-6849-1366)
- Sandra Nitsch
- Robert Schneider (ORCID: https://orcid.org/0000-0001-5303-0973)
- Tamás Schauer (ORCID: https://orcid.org/0000-0001-9602-4557)
- Juan Pablo (ORCID: https://orcid.org/0000-0002-3526-516X)
- A. E. Coraor (ORCID: https://orcid.org/0000-0001-7417-890X)
- Hendrik Dietz (ORCID: https://orcid.org/0000-0003-1270-3662)
- Jonas J. Funke
- Eva Richard (ORCID: https://orcid.org/0000-0001-9711-1417)
- Jianfeng Sun (ORCID: https://orcid.org/0000-0003-1498-957X)
- Federica Battistini (ORCID: https://orcid.org/0000-0002-7544-0938)
- R G Roeder
Institutions
- Northwestern University (US)
- Helmholtz Zentrum München (DE)
- University of Chicago (US)
- Institute for Research in Biomedicine (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Heinrich Heine University Düsseldorf (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- Universidad Autónoma de Madrid (ES)
- MTU Aero Engines (Germany) (DE)
- Ludwig-Maximilians-Universität München (DE)
- Rockefeller University (US)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1016/j.molcel.2025.11.030
- Citations
- 2
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.61