Histone Acylation beyond Acetylation: Terra Incognita in Chromatin Biology

Abstract

Histone acetylation, one of the first and best studied histone post-translational modifications (PTMs), as well as the factors involved in its deposition (writers), binding (readers) and removal (erasers), have been shown to act at the heart of regulatory circuits controlling essential cellular functions. The identification of a variety of competing histone lysine-modifying acyl groups including propionyl, butyryl, 2-hydroxyisobutyryl, crotonyl, malonyl, succinyl and glutaryl, raises numerous questions on their functional significance, the molecular systems that manage their establishment, removal and interplay with the well-known acetylation-based mechanisms. Detailed and large-scale investigations of two of these new histone PTMs, crotonylation and 2-hydroxyisobutyrylation, along with histone acetylation, in the context of male genome programming, where stage-specific gene expression programs are switched on and off in turn, have shed light on their functional contribution to the epigenome for the first time. These initial investigations fired many additional questions, which remain to be explored. This review surveys the major results taken from these two new histone acylations and discusses the new biology that is emerging based on the diversity of histone lysine acylations.

Keywords: Bromodomain; HAT; HDAC; Spermatogenesis; X Inactivation.

Fig.1

Molecular systems orbiting around histone acetylation have been the centre of comprehensive investigations leading to the identification and functional characterization of the three major classes of actors involved in generating [acetyltransferases ( HATs )], reading [bromodomains ( BRDs )] and erasing [deacetylases ( HDACs )] signalling to chromatin based on acetylation. In contrast, our knowledge of the molecular machinery managing signalling through histone acylations other than acetylation is very poor and only a few enzymes involved in their establishment and removal have been identified so far. All the acyl group donors are generated through cell metabolism and hence a critical question to address is how cell metabolism drives all these modifications and how it imposes a specific choice on the use of acyl group. Ac; Acetylation, Pr; Propionylation, Bu; Butyrylation, Hib; 2-hydroxyisobutyrylation, Cr; Crotonylation, Su; Succinylation, Glu; Glutarylation and CBP/p300; CREB-binding protein/EP300.