Rbm10 regulates inflammation development via alternative splicing of Dnmt3b

RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of...

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Bibliographic Details
Published in:International immunology 2017-12, Vol.29 (12), p.581-591
Main Authors: Atsumi, Toru, Suzuki, Hironao, Jiang, Jing-Jing, Okuyama, Yuko, Nakagawa, Ikuma, Ota, Mitsutoshi, Tanaka, Yuki, Ohki, Takuto, Katsunuma, Kokichi, Nakajima, Koichi, Hasegawa, Yoshinori, Ohara, Osamu, Ogura, Hideki, Arima, Yasunobu, Kamimura, Daisuke, Murakami, Masaaki
Format: Article
Language:English
Subjects:
Alternative Splicing - genetics
Animals
Arthritis - genetics
Arthritis - immunology
Cells, Cultured
Disease Models, Animal
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA Methyltransferase 3B
Humans
Inflammation - genetics
Inflammation - immunology
Mice
Mice, Inbred C57BL
NF-kappa B - metabolism
Protein Isoforms - genetics
RNA, Small Interfering - genetics
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Transcriptional Activation
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Summary:RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.
ISSN:0953-8178
1460-2377
DOI:10.1093/intimm/dxx067