Identification of Lysine Isobutyrylation as A New Histone Modification Mark

Abstract

Short-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity, especially p300 and HAT1. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

Epigenetic variation: A major player in facilitating plant fitness under changing environmental conditions

“…Three major types of epigenetic marks or signatures include DNA methylation, histone modifications, and small RNAs. During DNA methylation, the methyl groups get covalently bound to cytosine nucleotides (5 mC) (Bartels et al, 2018;Gomez-Cabellos et al, 2022) and along with covalent modifications like methylation, acetylation, and phosphorylation in histone proteins regulate the local chromatin landscape (Zhu et al, 2021;Tian et al, 2022). Non-coding small RNAs such as microRNAs play a significant role in post-transcriptional regulation directing DNA methylation and chromatin remodeling at their target loci (Bossdorf et al, 2008;Robertson and Wolf, 2012;Bond and Baulcombe, 2014;Ariel and Manavella, 2021).…”