Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution
Description
In addition to acetylation, histones are modified by a series of competing longer chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions have hindered the understanding of histone acylations’ specific roles. Here, by using an acute lymphoblastic leukaemia (ALL) cell model and blasts from B-ALL patients, we demonstrate a role for mitochondrial activity in controlling histone acylation/acetylation ratio, especially at H4K5. An increase of the ratio of non-acetyl acylation (crotonylation or butyrylation) over acetylation on H4K5 weakens BRD4 bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer chain acylation(s) ratio could constitute a common mechanism regulating the bromodomain factors’ functional genomic distribution.