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

Abstract

The intestine is inhabited by a large number of commensal bacteria that are immunologically non-self, potentially causing inflammation. However, in a healthy intestine, inflammation is strictly controlled at low levels to maintain homeostasis. We previously reported that the gut microbiota induce DNA methylation of the gene encoding Toll-like receptor (TLR) 4, a pattern recognition receptor that recognizes lipopolysaccharides of gram-negative bacteria, in colonic epithelial cells, suggesting its role in controlling intestinal inflammation. However, there remains a question of how gut microbiota cause methylation of only specific genes including TLR4, despite the fact that DNA methyltransferase (DNMT) is common to all genes targeted for methylation. Here, we identified RBM14 as an adaptor molecule that recruits DNMT to the TLR4 gene. RBM14 was shown to bind DNMT3 and be expressed at significantly higher levels in an intestinal epithelial cell (IEC) line with hypermethylated TLR4 gene than in an IEC line with hypomethylated TLR4 gene. In addition, RBM14 interacted with DNA regions of the TLR4 gene, and knockdown of RBM14 suppressed DNA methylation of the TLR4 gene in IECs. Furthermore, RBM14 expression was higher in colonic epithelial cells of conventional mice than in those of germ-free mice. Collectively, these results indicate that the gut microbiota induce methylation of the TLR4 gene in colonic epithelial cells by upregulating RBM14, which can recruit DNMT3 to the gene. The regulation of adaptor molecules such as RBM14, which bind to specific target genes and recruit DNMT, can explain, at least in part, how gut microbiota contribute to the maintenance of intestinal homeostasis through epigenetic control of specific gene expression in IECs.

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets

“…These genes are likely linked to autoimmune skin diseases and inflammatory skin conditions 67,68 Epigenetic regulation and gene expression: HDAC5 and RBM14 are involved in epigenetic modifications and gene regulation, potentially influencing a range of skin processes, such as aging, development and differentiation 69,70 Cell signalling and cytoskeletal remodelling: NCK1 and CBY1 play roles in cell signalling and cytoskeletal remodelling, which are crucial for preserving the structural integrity and functionality of skin cells. Cellular processes and transport: DCTN1 and MYO19 participate in cellular processes, such as protein transport and organelle movement.…”

Gut microbiota induced epigenetic modifications in the non‐alcoholic fatty liver disease pathogenesis

“…Dysregulation of epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAmediated regulation, can contribute to the development and progression of NAFLD [52]. More recently, gut microbiota have been identified as important factors that significantly influence the host epigenetic landscape in NAFLD pathogenesis [49][50][51][53][54][55][56], highlighting the need for further research in this area to develop new therapeutic strategies. Gut microbiota can modulate the host's epigenetic landscape in the context of NAFLD through various mechanisms.…”

“…Recent research has revealed that the gut microbiota can modulate the host's epigenetic landscape through bacterial components and microbial metabolites. Dysbiosis of gut microbiota may lead to aberrant epigenetic modifications, such as DNA methylation and histone modifications, which can affect gene expression and contribute to the pathogenesis of NAFLD [ 49 , 50 , 51 ]. Therefore, in this review, we will focus on the evidence suggesting that the gut microbiome influences the pathogenesis of NAFLD by manipulating epigenetic mechanisms.…”

“…For instance, a Firmicutes‐dominant gut microbiome in pregnant women has been linked to differential gene promoter methylation, which is associated with lipid metabolism and obesity [ 57 ]. Additionally, gut microbiota can maintain intestinal immunological homeostasis by epigenetically altering toll‐like receptor 4 DNA methylation through recruiting DNA methyltransferase (DNMT) 3 in intestinal epithelial cells (IECs), which play a crucial role in the development of hepatic fibrosis and steatosis [ 49 , 58 ]. Moreover, the gut microbiota influences host epigenetics in NAFLD by modulating one‐carbon metabolism, supplying methyl groups like folate and choline for DNA methylation.…”

The role of the glycome in symbiotic host-microbe interactions

“…TLRs, for example, were initially discovered for their role in the host development ( Anthoney et al 2018 ). Signalling through TLR4, which recognises one of the most potent inducers of innate immunity, LPS, suppresses inflammatory reactions in colonic epithelial cells ( Narabayashi et al 2022 ). The same type of signalling via LPS from the gut commensal Bacteroides vulgatus , with a weak agonistic activity, extinguishes intestinal inflammation and restores gut immune homeostasis ( Steimle et al 2019 ).…”