Regulation of Gene Expression through Gut Microbiota-Dependent DNA Methylation in Colonic Epithelial Cells

Abstract

A huge number of commensal bacteria inhabit the intestine, which is equipped with the largest immune system in the body. Recently, the regulation of various physiological functions of the host by these bacteria has attracted attention. In this study, the effects of commensal bacteria on gene expression in colonic epithelial cells (CoECs) were investigated with focus on regulation of DNA methylation. RNA sequencing analyses of CoECs from conventional, germ-free, and MyD88 2/2 mice indicated that, out of the genes affected by commensal bacteria, those downregulated in a MyD88-independent manner were most frequently observed. Furthermore, when the 59 regions of genes downregulated by commensal bacteria in CoECs were captured using a customized array and immunoprecipitated with the anti-methyl cytosine Ab, a certain population of these genes was found to be highly methylated. Comprehensive analysis of DNA methylation in the 59 regions of genes in CoECs from conventional and germ-free mice upon pulldown assay with methyl-CpG-binding domain protein 2 directly demonstrated that DNA methylation in these regions was influenced by commensal bacteria. Actually, commensal bacteria were shown to control expression of Aldh1a1, which encodes a retinoic acid-producing enzyme and plays an important role in the maintenance of intestinal homeostasis via DNA methylation in the overlapping 59 region of Tmem267 and 3110070M22Rik genes in CoECs. Collectively, it can be concluded that regulation of DNA methylation in the 59 regions of a specific population of genes in CoECs acts as a mechanism by which commensal bacteria have physiological effects on the host.

Dietary Goji Shapes the Gut Microbiota to Prevent the Liver Injury Induced by Acute Alcohol Intake

“…It is a naturally occurring, biologically active metabolite of vitamin A. Retinol is vital to maintaining the integrity of the epithelium and mucous membranes ( 60 ). Previous studies showed that symbiotic bacteria produced retinol derivatives that could protect the intestinal epithelial barrier ( 61 , 62 ). Besides, Goji and its trained microbiota also upregulated the levels of L-glutamic acid and pyroglutamic acid, which are involved in GSH metabolism.…”

Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions

“…Interestingly, in the colon, which has a larger population of commensal bacteria compared to the small intestine, DNA methylation of the TLR4 gene in IECs depends on gut microbiota, indicating that commensal bacteria themselves maintain the symbiotic environment by causing epigenetic changes in host cells (Takahashi et al, 2011). In addition, we observed that the 5′ regions of specific populations of genes whose expression is downregulated by gut microbiota are highly methylated in colonic epithelial cells, suggesting that induction of DNA methylation serves as a mechanism by which the gut microbiota can regulate gene expression in IECs (Takahashi et al, 2020). However, the precise underlying molecular mechanisms remain to be elucidated.…”

Intestinal Microbiota: Novel Personalized Cancer Immunotherapy in Colorectal Cancer

“…Superficial colonocytes lining intestinal crypts absorb SCFAs as energy and subsequently, impede diffusion to the stem cell niche where stem cell proliferation is suppressed by these metabolites [188]. The interplay between IECs and the microbiota entails the regulation of HDACs and alteration of host epigenome in order to reinforce gene expression and barrier function [189]. Intestinal homeostasis and barrier integrity is sustained when HDAC is expressed in IECs.…”

“…Histone or nonhistone proteins are cleared of acetyl residues by HDACs. Massive protein complexes are home to such epigenomic-modifying enzymes that are directed towards target chromatin by means of transcription factor interactions [189][190][191].…”