Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution II

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 crotonylation and butyrylation over acetylation on H4K5 weakens BRD4-chromatin interaction and increases BRD4 nuclear mobility and availability for binding transcription start site associated nucleosome free regions of active genes. Our data suggest that, with regard to BRD4 dynamics, histone acylations including acetylation, should be considered collectively. A metabolism dependant control of the histone acetylation/longer chain acylation(s) ratio could constitute a common mechanism regulating bromodomain factors' “reservoir” pool, availability and functional genomic distribution. Overall design: Chromatin immunoprecipitation assays and sequencing (ChIPseq) of REH cells (WT and FASTKD1 ko) with anti-BRD4