Metabolic regulation of gene expression through histone acylations

Abstract

Eight types of short-chain lysine (Lys) acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggest that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, acylation “reader” proteins that mediate the effects of different acylations, and their physiological functions, including in signal-dependent gene activation, spermatogenesis, tissue injury and metabolic-induced stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by metabolism of the different acyl-CoA forms, which in turn modulate the regulation of gene expression.

Intricate Effects of α-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4

“…Since the rates of crotonylation, butyrylation, and propionylation by p300 are extremely low (3-fold to as much as 62-fold) in comparison to acetylation, 34 there may be a metabolic component that involves increasing short chain acyl-CoA concentrations and/or a non-enzymatic mechanism to regulate the diversity and levels of protein lysine acylations. 35, 36 Methylation of H4K5 exists in vivo and is catalyzed by the lysine methyltransferase SET5 in yeast and by the SET and MYND domain-containing protein 3 (SMYD3) in human. 37, 38 Moreover, while SMYD3 is able catalyze mono-, di-, and trimethylation of H4K5 as well as monomethylation of H4K12, the major product of SMYD3 is monomethylated H4K5.…”

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

“…Numerous CoA thioesters are also involved in the post-translational modification of histones and thousands of other proteins (1)(2)(3)(4)(5). Three major subcellular CoA pools are found in the cytosol, mitochondria, and peroxisomes to support specific metabolic pathways (6,7).…”

“…These include, among others, fatty acid synthesis in the cytosol, the TCA cycle and oxidation of longchain and medium-chain fatty acids in the mitochondria, and bile acid conjugation and oxidation of very long-chain and branched-chain fatty acids in the peroxisomes. A dedicated pool of acetyl-CoA is also found in the endoplasmic reticulum where it is involved in protein quality control and autophagy (8), while nuclear acylCoAs, which freely equilibrate with the cytosolic pool across the nuclear pores, contributes to the regulation of gene expression (5).…”

Introductory Chapter: Current Studies in Transcriptional Control System; Toward the Establishment of Therapies against Human Diseases

“…The result suggests that the transcription elongation machinery could be an effective therapeutic target. It was recently reported that ENL protein, which possesses acetyl lysine recognizing YEATS domain [30], acts as an activator of leukemia-diving factor encoding gene expression [53,54]. Therefore, targeting the ENL protein could be an effective therapeutic strategy against aggressive leukemia.…”

“…In addition, they are acylated on the Lys residues to regulate transcription of genes that encode metabolic-response factors [30]. These modifications are recognized by different proteins, such as bromodomaincontaining proteins [31], double PHD finger domain proteins [30,32], YEATS domain proteins [30], WD40 proteins [33], and Ankyrin-repeat proteins [34].…”