Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Abstract

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

“…To substantiate this, we analyzed KAT8 is the catalytic subunit of 2 multiprotein complexes important for genome-wide epigenetic regulation (Supplemental Figure 10B) (48,49), raising the intriguing question of how they contribute to the critical role of KAT8 in regulating cerebral development ( Figure 8E). Subunits of the complexes are well expressed in the cerebral cortex of neonatal mice and neurospheres cultured from mouse embryos (Supplemental Figure 1, B and C) this, inducible Kat8 deletion triggers apoptosis in myeloid cells (47). Cerebrum-specific Kat8 deletion affected NSPC proliferation ( Figure 4) and neurogenesis at E13.5 (Figure 2A), but not so obvious E12.5 ( Figure 2B and Supplemental Figure 5A), indicating context-dependent effects.…”

Post-Translational Modifications in NETosis and NETs-Mediated Diseases

“…Histone methylation (histone H3 lysine 9 (H3K9)) is extensively present in CD34 + cells, but decreases to minimal levels as the neutrophil matures [15]. Other histone acetylation (H4K16) was also found to be significantly induced in mature neutrophils [16]. Therefore, understanding the role of PTM in neutrophils is a must, as chromatin change during maturation can result in a major transition in genome functioning [17].…”

“…In fact, mature neutrophils only contain two Bcl-2 pro-survival proteins, Mcl-1 and A1 [49]. Also, apoptosis can be regulated through PTM, as histone acetylation (H4K16), for example, was shown to be enriched at specific DNA repeats which generated 50 kb DNA fragments during the first stages of programmed cell death in neutrophils [16].…”

Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations

“…Histone H4, encoded by HIST1H4A, is one of the five main histone proteins involved in gene regulation, DNA repair, and chromatin structure. 38 Histone H4 mutations remain understudied in human diseases, including cancers. Figure 5a shows multiple potential PPI-perturbing mutations on histone H4 in complex with DAXX (deathassociated protein 6), H3F3A (H3 histone family member 3A), and CENPA (centromere protein A).…”