Regulation of Carbohydrate-Responsive Metabolic Genes by Histone Acetylation and the Acetylated Histone Reader BRD4 in the Gene Body Region.

Kazuki Mochizuki,Natsuyo Hariya,Shiori Ishiyama,Toshinao Goda

doi:10.3389/fmolb.2021.682696

Abstract

Studies indicate that induction of metabolic gene expression by nutrient intake, and in response to subsequently secreted hormones, is regulated by transcription factors binding to cis-elements and associated changes of epigenetic memories (histone modifications and DNA methylation) located in promoter and enhancer regions. Carbohydrate intake-mediated induction of metabolic gene expression is regulated by histone acetylation and the histone acetylation reader bromodomain-containing protein 4 (BRD4) on the gene body region, which corresponds to the transcribed region of the gene. In this review, we introduce carbohydrate-responsive metabolic gene regulation by (i) transcription factors and epigenetic memory in promoter/enhancer regions (promoter/enhancer-based epigenetics), and (ii) histone acetylation and BRD4 in the gene body region (gene body-based epigenetics). Expression of carbohydrate-responsive metabolic genes related to nutrient digestion and absorption, fat synthesis, inflammation in the small intestine, liver and white adipose tissue, and in monocytic/macrophage-like cells are regulated by various transcription factors. The expression of these metabolic genes are also regulated by transcription elongation via histone acetylation and BRD4 in the gene body region. Additionally, the expression of genes related to fat synthesis, and the levels of acetylated histones and BRD4 in fat synthesis-related genes, are downregulated in white adipocytes under insulin resistant and/or diabetic conditions. In contrast, expression of carbohydrate-responsive metabolic genes and/or histone acetylation and BRD4 binding in the gene body region of these genes, are upregulated in the small intestine, liver, and peripheral leukocytes (innate leukocytes) under insulin resistant and/or diabetic conditions. In conclusion, histone acetylation and BRD4 binding in the gene body region as well as transcription factor binding in promoter/enhancer regions regulate the expression of carbohydrate-responsive metabolic genes in many metabolic organs. Insulin resistant and diabetic conditions induce the development of metabolic diseases, including type 2 diabetes, by reducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in white adipose tissue and by inducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in the liver, small intestine, and innate leukocytes including monocytes/macrophages and neutrophils.

Highlights

Excessive carbohydrate intake, in particular digested carbohydrates, and excessive intake of other energy nutrients including fat and protein, leads to the development and progression of life-style diseases including obesity, type 2 diabetes, and related complications
Yamada et al demonstrated that force-feeding mice fructose induces the expression of many lipid accumulation-related genes including Cyp8b1, Dak, and Plin5 as well as bromodomain-containing protein 4 (BRD4) binding and histone acetylation on the gene body and promoter/enhancer regions of those genes in mouse liver (Yamada et al, 2016)
Carbohydrate intake induces histone acetylation of the gene body region rather than transcription factor binding, e.g., caudal-type homeobox 2 (CDX2) and hepatocyte nuclear factor 1 (HNF1), and this acetylation has been observed for carbohydrate digestion/absorption-related genes such as Si and Sglt1 in the small intestine of mice and rats (Honma et al, 2007; Inoue et al, 2011)

Summary

Introduction

In particular digested carbohydrates, and excessive intake of other energy nutrients including fat and protein, leads to the development and progression of life-style diseases including obesity, type 2 diabetes, and related complications. BRD4 binds to acetylated histones on the gene body and proximal promoter regions to enhance transcription elongation by phosphorylating the second serine residue of the C-terminal domain (CTD) of RNA polymerase II and/or recruiting P-TEFb, a cyclin T1-CDK9 complex (Jang et al, 2005) (Figure 4).

Results

Conclusion