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

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 hinder our understanding of histone acylations' specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (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 be a common mechanism regulating the bromodomain factors' functional genomic distribution.

Automated summary

This study shows that mitochondrial activity can regulate the balance between histone acetylation and longer-chain acylations, impacting the function of histone H4K5. An increase in non-acetyl acylations over acetylation weakens the chromatin interaction of bromodomain containing protein 4 (BRD4), leading to enhanced nuclear mobility and binding at transcription start sites of active genes. This suggests that metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio may be a common mechanism regulating the genomic distribution of bromodomain factors.