Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity

Meng Xia, Juan Liu, Shuxun Liu, Kun Chen, Hongyu Lin, Minghong Jiang, Xiaoqing Xu, Yiquan Xue, Wei Liu, Yan Gu, Xiang Zhang, Zhiqing Li, Lin Yi, Youcun Qian, Chen Zhou, Ru Li, Xuan Zhang, Zhanguo Li and Xuetao Cao ()
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Meng Xia: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences
Juan Liu: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Shuxun Liu: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Kun Chen: Institute of Immunology, Zhejiang University School of Medicine
Hongyu Lin: Institute of Immunology, Zhejiang University School of Medicine
Minghong Jiang: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences
Xiaoqing Xu: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences
Yiquan Xue: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Wei Liu: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences
Yan Gu: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Xiang Zhang: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Zhiqing Li: Institute of Immunology, Zhejiang University School of Medicine
Lin Yi: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University
Youcun Qian: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Chen Zhou: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
Ru Li: Peking University People’s Hospital
Xuan Zhang: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
Zhanguo Li: Peking University People’s Hospital
Xuetao Cao: National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-β-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription. After TGF-β stimulation, activated Smad3 suppresses lnc-Smad3 transcription, thereby recovering the Smad3 promoter accessibility to Ash1l. By revealing the opposite regulatory functions of Ash1l and lnc-Smad3 in Smad3 expression, our data provide insights for the epigenetic control of Treg cell fate to potentially aid in the development of therapeutic intervention for autoimmune diseases.

Date: 2017
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DOI: 10.1038/ncomms15818

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