Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark

Abstract

We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr). This histone mark was initially identified by MS and then validated by chemical and biochemical methods. Histone Khib shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. Using chromatin immunoprecipitation sequencing, gene expression analysis and immunodetection, we show that in male germ cells, H4K8hib is associated with active gene transcription in meiotic and post-meiotic cells. In addition, H4K8ac-associated genes are included in and constitute only a subfraction of H4K8hib-labeled genes. The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change. These findings suggest its critical role on the regulation of chromatin functions.

Structural Basis of the Stereospecificity of Bacterial B12-dependent 2-Hydroxyisobutyryl-CoA Mutase

“…shermanii (PfMCM) (13,14). These studies showed that binding of the acyl-CoA substrate results in a large conformational change that causes the formation of an initial radical by homolysis of the adenosylcobalamin-cobalt bond in the coenzyme B 12 . This 5Ј-deoxyadenosyl radical abstracts a hydrogen atom from the substrate (Fig.…”

“…Coenzyme B 12 -dependent acyl-CoA mutases are a relatively small family of enzymes catalyzing carbon skeleton rearrangements through a unique radical mechanism (1). Thus far, methylmalonyl-CoA mutase (MCM), 5 ethylmalonyl-CoA mutase (ECM), and isobutyryl-CoA mutase (ICM) have been characterized (2)(3)(4).…”

“…This unusual short-chain carboxylic acid is formed during degradation of xenobiotic fuel oxygenates (10) but is also found in humans with lactic acidosis (11), and lysine 2-hydroxyisobutyrylation has recently been identified as a widely distributed histone mark (12). Besides these characterized enzymes, several not yet identified B 12 -dependent mutases have been postulated to be involved in microbial degradation pathways for the anaerobic mineralization of alkanes and ethylbenzene (8), indicating that different subfamilies of acyl-CoA mutases may exist as key enzymes in microbial degradation pathways of natural compounds as well as xenobiotics.…”

Histone modifications in DNA damage response

“…Histones are easily catalyzed by histone modification enzymes to form different kinds of posttranslational modifications, such as methylation, acetylation and phosphorylation (Campos and Reinberg, 2009;Kouzarides, 2007). Until now, more than a dozen types of histone modifications and hundreds of modification sites altogether have been found (Arnaudo and Garcia, 2013;Dai et al, 2014;Kouzarides, 2007;Tan et al, 2011) (Figure 1). …”

Touch, act and go: landing and operating on nucleosomes

“…While DNA is affected by methylation and derived chemical modifications of cytosine residues, histone proteins are subject to a variety of post-translational modifications that include, but are not limited to, methylation of lysines and arginines, phosphorylation of serine and tyrosine residues, acetylation, crotonylation and butyrylation as well as ubiquitination of lysines. An extensive overview of the chemistry and effective role in chromatin regulation for these and other modifications can be found in recently published works and reviews by different research groups (Tan et al, 2011;Dai et al, 2014;Tessarz & Kouzarides, 2014;Bowman & Poirier, 2015;McGinty & Tan, 2015). Despite their different nature and effect, all these modifications are installed, recognized or removed by dynamic processes, which affect and control chromatin accessibility, gene regulation and activity, as well as the repair of damaged DNA, key to maintaining genome stability.…”