Abstract
Type 2 diabetes (T2D) is a major chronic healthcare concern worldwide. Emerging evidence suggests that a histone-modification-mediated epigenetic mechanism underlies T2D. Nevertheless, the dynamics of histone marks in T2D have not yet been carefully analyzed. Using a mass spectrometry-based label-free and chemical stable isotope labeling quantitative proteomic approach, we systematically profiled liver histone post-translational modifications (PTMs) in a prediabetic high-fat diet-induced obese (DIO) mouse model. We identified 170 histone marks, 30 of which were previously unknown. Interestingly, about 30% of the histone marks identified in DIO mouse liver belonged to a set of recently reported lysine acylation modifications, including propionylation, butyrylation, malonylation, and succinylation, suggesting possible roles of these newly identified histone acylations in diabetes and obesity. These histone marks were detected without prior affinity enrichment with an antibody, demonstrating that the histone acylation marks are present at reasonably high stoichiometry. Fifteen histone marks differed in abundance in DIO mouse liver compared with liver from chow-fed mice in label-free quantification, and six histone marks in stable isotope labeling quantification. Analysis of hepatic histone modifications from metformin-treated DIO mice revealed that metformin, a drug widely used for T2D, could reverse DIO-stimulated histone H3K36me2 in prediabetes, suggesting that this mark is likely associated with T2D development. Our study thus offers a comprehensive landscape of histone marks in a prediabetic mouse model, provides a resource for studying epigenetic functions of histone modifications in obesity and T2D, and suggest a new epigenetic mechanism for the physiological function of metformin.
Highlights
From the ‡The Chemical Proteomics Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China, 201203; §State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China, 201203; ¶University of Chinese Academy of Sciences, Beijing 100049, P
We report a comprehensive analysis of histone modifications in liver tissues from diet-induced obese (DIO) mice and metformin-treated DIO (DIO-Met) mice using a mass spectrometry-based label-free and chemical stable isotope labeling quantitative proteomic approach
We chose liver tissues from DIO and chow-fed mice to study histone marks because aberrant hepatic gluconeogenesis is considered a predominant factor in Type 2 diabetes (T2D) development
Summary
SIRT1 regulates glucose homeostasis by affecting diverse protein targets, such as forkhead box O (FOXO) transcription factors, PPAR-␥ coactivator PGC-1␣, Molecular & Cellular Proteomics 16.7 and mitochondrial uncoupling protein 2 (UCP2), to control insulin secretion, gluconeogenesis, and mitochondrial metabolism [4, 8]. Jhdm1a, a histone H3K36 demethylase, regulates gluconeogenesis by suppressing expression of the master gluconeogenic regulator C/EBP␣ [11]. These previous efforts are mainly focused on a few widely studied histone marks and their corresponding regulatory enzymes. Hepatic SIRT1, a lysine deacetylase, and GCN5, a lysine acetyltransferase, were reported to be regulated by metformin to suppress gluconeogenesis via deacetylation of transcription coactivator 2 (TORC2) and PGC-1␣, respectively [14]. Changes in histone marks in response to metformin have not been fully examined to date
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
