Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues.

Zhe Wang,Meng Wang,Ming Zhu,Chao Zhang,Cong Zhang,Yihui Gao,Shen Qu,Shangyun Liu,Zhongmin Liu

doi:10.3389/fgene.2021.650863

Abstract

BackgroundThe number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.ObjectiveIn this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. We also aimed to elucidate the correlation of these genes that modulated by histone modification with energy metabolism and inflammation under both short-term and long-term HFD conditions.MethodWe performed ChIP-seq analysis of H3K9me2 and H3K9me3 in brown and white adipose tissues (WATs; subcutaneous adipose tissue) from mice fed with a standard chow diet (SCD) or HFD and a composite analysis of the histone modification of H3K9me2, H3K9me3, H3K4me1 and H3K27ac throughout the whole genome. We also employed and integrated two bulk RNA-seq and a single-nuclei RNA sequencing dataset and performed western blotting (WB) to confirm the gene expression levels in adipose tissue of the SCD and HFD groups.ResultsThe ChIP-seq and transcriptome analysis of mouse adipose tissues demonstrated that a series of genes were activated by the histone modification of H3K9me2, H3K9me3, H3K4me1, and H3K27ac in response to HFD condition. These genes were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in lipogenesis, energy metabolism and inflammation. Several genes in the activated mitogen-activated protein kinase (MAPK) pathway might be related to both inflammation and energy metabolism in mice, rats and humans fed with HFD for a short or long term, as showed by bulk RNA-seq and single nuclei RNA-seq datasets. Western blot analyses further confirmed the increased expression of MET, VEGFA and the enhanced phosphorylation ratio of p44/42 MAPK upon HFD treatment.ConclusionThis study expanded our understanding of the influence of eating behavior on obesity and could assist the identification of putative therapeutic targets for the prevention and treatment of metabolic disorders in the future.

Highlights

As one of the world’s greatest health challenges, obesity is usually accompanied by an increased risk for many chronic diseases, including type 2 diabetes, cardiovascular, hypertension and dyslipidemia
The peak fold enrichment of H3K9me2 and H3K9me3 modifications was decreased in both the brown adipose tissue (BAT) and white adipose tissue (WAT) of high-fat diet (HFD) fed mice compared with those of standard chow diet (SCD) fed mice (Figures 1C,D). These results suggested a decreased level of H3K9 methylation crossing the whole genome in HFD fed mice compared with SCD fed group
The KEGG enrichment analysis revealed that the genes with H3K9 demethylation modification in adipose tissue of the HFD-fed mice were enriched in pathways related to lipogenesis, energy metabolism, immunity and inflammation (Figure 2A)

Summary

Introduction

As one of the world’s greatest health challenges, obesity is usually accompanied by an increased risk for many chronic diseases, including type 2 diabetes, cardiovascular, hypertension and dyslipidemia. As the link between genetic variants and environmental factors, the role of epigenetic modifications in obesity, including histone modifications, DNA methylation and non-coding RNA, had gained much attention in the late decade. Metabolic diseases, such as obesity and diabetes, were found to be tightly associated with epigenetic variation (Ling and Ronn, 2019). Same histone could involve various modifications of several chemical groups, such as methylation and acetylation (Okuno et al, 2013), to activate or repress gene expression. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes

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Conclusion