Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions
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 DN...
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1005136/full |
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| author | Hikari Narabayashi Chiharu Koma Kazuaki Nakata Mion Ikegami Yusuke Nakanishi Jun Ogihara Masato Tsuda Akira Hosono Shigemasa Hanazawa Kyoko Takahashi |
| author_facet | Hikari Narabayashi Chiharu Koma Kazuaki Nakata Mion Ikegami Yusuke Nakanishi Jun Ogihara Masato Tsuda Akira Hosono Shigemasa Hanazawa Kyoko Takahashi |
| author_sort | Hikari Narabayashi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T08:40:40Z |
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| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-11T08:40:40Z |
| publishDate | 2022-10-01 |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-214176f620144540b28682d397f6aebf2022-12-22T04:34:12ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-10-01910.3389/fmolb.2022.10051361005136Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactionsHikari Narabayashi0Chiharu Koma1Kazuaki Nakata2Mion Ikegami3Yusuke Nakanishi4Jun Ogihara5Masato Tsuda6Akira Hosono7Shigemasa Hanazawa8Kyoko Takahashi9Department of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanDepartment of Applied Biological Science, College of Bioresource Sciences, Nihon University, Fujisawa, JapanThe 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.https://www.frontiersin.org/articles/10.3389/fmolb.2022.1005136/fullgut microbiotaintestinal epithelial cellTLR4DNA methyltransferaseRBM14 |
| spellingShingle | Hikari Narabayashi Chiharu Koma Kazuaki Nakata Mion Ikegami Yusuke Nakanishi Jun Ogihara Masato Tsuda Akira Hosono Shigemasa Hanazawa Kyoko Takahashi Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions Frontiers in Molecular Biosciences gut microbiota intestinal epithelial cell TLR4 DNA methyltransferase RBM14 |
| title | Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions |
| title_full | Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions |
| title_fullStr | Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions |
| title_full_unstemmed | Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions |
| title_short | Gut microbiota-dependent adaptor molecule recruits DNA methyltransferase to the TLR4 gene in colonic epithelial cells to suppress inflammatory reactions |
| title_sort | gut microbiota dependent adaptor molecule recruits dna methyltransferase to the tlr4 gene in colonic epithelial cells to suppress inflammatory reactions |
| topic | gut microbiota intestinal epithelial cell TLR4 DNA methyltransferase RBM14 |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1005136/full |
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