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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Autoimmunity*
  • Cell Polarity*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Gene Silencing
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / immunology
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / immunology*
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / immunology
  • Smad3 Protein / genetics*
  • Smad3 Protein / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transforming Growth Factor beta / immunology

Substances

  • DNA-Binding Proteins
  • Histones
  • RNA, Long Noncoding
  • Smad3 Protein
  • Transcription Factors
  • Transforming Growth Factor beta
  • ASH1L protein, human
  • Ash1l protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Histone Deacetylase 1