NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

Abstract

Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…Whereas class I HDACs show little substrate specificity and the direct HDAC activity of class II HDACs has been debated, the class III HDAC SIRT1 has been reported to show preference for deacetylation of H4K16 (Vaquero et al, 2004(Vaquero et al, , 2007Pruitt et al, 2006). Further, HDACs 1-8 were ubiquitously expressed in H157 cells as assessed by immunoblotting, and did not show any change in expression after VPA or TSA exposure (data not shown).…”

“…We therefore examined the effects of TSA and VPA exposure on SIRT1 protein levels ( Figure 5a). In addition, we analyzed the protein levels of hMOF and SIRT2, a cytoplasmic HDAC that has been shown to deacetylate H4K16Ac during mitosis (Vaquero et al, 2006(Vaquero et al, , 2007. SIRT1, SIRT2 and hMOF proteins were all expressed in untreated cells.…”

High-resolution mapping of H4K16 and H3K23 acetylation reveals conserved and unique distribution patterns inArabidopsisand rice

“…27 In contrast, acetylation of lysine 16 of histone H4 (H4K16ac) appears to have unique and distinct functions from other acetylation marks. 28,29 In budding yeast, hypoacetylated H4K16 is critical for maintaining the proper heterochromatin boundaries 30,31 and is implicated as a central switch for high-order chromatin compaction. 29,[32][33][34] Yeast hyperacetylation of H4K16 at specific subtelomeric regions is also correlated with lifespan.…”

CRISPR-based reagents to study the influence of the epigenome on gene expression

“…Class I HDACs tend to be expressed ubiquitously and compartmentalized to the nucleus 32, whereas class IIA/IIB and 4 shows some cell type restriction; these proteins have a zinc‐dependent catalytic domain 33 (class III HDACs are the sirtuins, which are NAD + ‐dependent 34.…”