Histone acylation in the epigenomic regulation of insulin action and metabolic disease

Abstract Posttranslational covalent histone modifications (PTMs), including acetylation, methylation and phosphorylation; and DNA methylation on cytosines are critical mechanisms of regulation of chromatin structure and transcriptional competence. The occurrence of histone PTMs, regulated by a plethora of dedicated enzymes, also relies upon the availability of the relative enzymatic substrates, AcetylCoA, S-adenosylmethionine, and ATP among others, which are at the same time the main energy carrying metabolic molecules. Insulin is the principal hormone regulating anabolic metabolism, exerting its pleiotropic actions by acting on insulin-sensitive tissues. Besides a direct action on metabolic fluxes, insulin extensively modulates gene expression. The relevance of insulin-dependent gene regulation has been confirmed by the observation that with insulin resistance and type 2 diabetes, insulin-regulated gene expression is impaired. In this chapter, we provide an overview of the current knowledge on the link between the hormonal action of insulin, via its intracellular signaling pathways, and the influence of these pathways on epigenetic modifications that act as central regulators of insulin-dependent gene transcription. We discuss the link between insulin signaling and transcriptional control via histone acetylation, and the more recently discovered multiple histone acylations and other novel epigenetic marks. The occurrence of alterations of proper acetylation and acylation patterns within the context of insulin resistance and type 2 diabetes will also be discussed. Reversing these alterations might provide novel therapeutic options against insulin resistance and/or type 2 diabetes.