Metabolic regulation of gene expression through histone acylations

Key Points Eight new types of histone short-chain Lys acylations have been discovered in the past few years, which include Lys propionylation (Kpr), Lys butyrylation (Kbu), Lys 2-hydroxyisobutyrylation (Khib), Lys succinylation (Ksucc), Lys malonylation (Kma), Lys glutarylation (Kglu), Lys crotonylation (Kcr) and Lys β-hydroxybutyrylation (Kbhb). Histone Lys acylations are regulated by acyltransferases and deacylases. Histone Lys acylations are modulated by the cellular metabolism of cognate short-chain acyl-CoA species. The novel histone Lys acylations are recognized by specific protein domains and can be differentiated from Lys acetylation. Histone Lys acylations mark transcriptionally active genes and function in different physiological processes, such as signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. In addition to acetylation, eight types of structurally and functionally different short-chain acylations have recently been identified as important histone Lys modifications: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These modifications are regulated by enzymatic and metabolic mechanisms and have physiological functions, which include signal-dependent gene activation and metabolic stress. Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests 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, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.