Article: Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation.
bioRxiv : the preprint server for biology
2023
Abstract: Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their ... ...
| Abstract | Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain size |
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| Language | English |
| Publishing date | 2023-09-29 |
| Publishing country | United States |
| Document type | Preprint |
| DOI | 10.1101/2023.09.29.560141 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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