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Nat Commun. 2017 Jun 9;8:15818. doi: 10.1038/ncomms15818.

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

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National Key Laboratory of Medical Molecular Biology, Department of Immunology &Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100032, China.
Department of Rheumatology &Immunology, Peking University People's Hospital, Beijing 100044, China.


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.

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