The Landscape of Histone Modifications in a High-Fat Diet-Induced Obese (DIO) Mouse Model

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.

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

“…It has been reported that high glucose alters the gene expression by methylation or acetylation of lysine residues on histone H3. A recent report showed the involvement of H3K36me2, H3K27me3, H3K9me2, and H3K23ac in metabolic disorder . We also show that there is increased K36 di‐methylation of histone H3 in HFD + low dose STZ‐induced diabetic conditions and this elevation was suppressed by l ‐Met‐S as well as metformin treatment.…”

“…Posttranslational histone modifications such as acetylation, methylation, phosphorylation, sumoylation, or ubiquitination also affect the expression of various genes associated with autoimmunity, carcinogenesis, and diabetes . Recent studies have shown an increase in global H3K4 monomethylation, H3K9 dimethylation, and H3K36 dimethylation in the liver tissue under diabetic conditions . The transcription factor, Forkhead box protein O1 (FOXO1), is a key regulator of insulin pathway and controls the expression of various genes involved in hepatic glucose metabolism .…”

Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty

“…Because the composition of the distribution of glycans that occupy a glycosite cannot be predicted from genomic data, quantification of glycopeptides from MS2 fragment ions is not straightforward and requires specialized bioinformatics tools. Quantitative proteomics methods including Skyline (31) allow a range of fixed chemical modifications to proteins, including phosphorylation, acetylation, methylation and acylation, among others (47)(48)(49)(50)(51). The landscape for quantitative glycoproteomics software, which must be able to handle a distribution of glycoforms at each glycosite, is far more limited.…”

ssc‐miR‐204 regulates porcine preadipocyte differentiation and apoptosis by targeting TGFBR1 and TGFBR2

“…22 The TGF-β signaling pathway regulates glucose tolerance and energy homeostasis, and the modulation of TGF-β activity could be an effective treatment strategy for diabetes and, especially importantly, for obesity. Epigenetic factors, including histone modifications, 27 noncoding RNA activity, 28 and DNA methylation, 29 are involved in gene regulation. Previous research using luciferase reporter assays has shown that TGFBR1 and TGFBR2 are potential targets of miR-204.…”

“…Many factors contribute to obesity, including epigenetic, genomic, and environmental factors. Epigenetic factors, including histone modifications, 27 noncoding RNA activity, 28 and DNA methylation, 29 are involved in gene regulation. miRNAs have been shown to be involved in a variety of biological functions.…”