The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.
CD4(+)Foxp3(+) regulatory T (T(reg)) cells are important for maintaining immune tolerance. Understanding the molecular mechanism that regulates T(reg) differentiation will facilitate the development of effective therapeutic strategies against autoimmune diseases. We report here that the SUMO E3 ligase PIAS1 restricts the differentiation of natural T(reg) cells by maintaining a repressive chromatin state of the Foxp3 promoter. PIAS1 acts by binding to the Foxp3 promoter to recruit DNA methyltransferases and heterochromatin protein 1 for epigenetic modifications. Pias1 deletion caused promoter demethylation, reduced histone H3 methylation at Lys(9), and enhanced promoter accessibility. Consistently, Pias1(-/-) mice displayed an increased natural T(reg) cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Our studies have identified an epigenetic mechanism that negatively regulates the differentiation of natural T(reg) cells.
Division of Hematology-Oncology, Department of Medicine, 11-934 Factor Building, 10833 Le Conte Avenue, University of California, Los Angeles, Los Angeles, CA 90095, USA. bliu@ucla.edu
Bin
B
Liu
Samuel
S
Tahk
Kathleen M
KM
Yee
Guoping
G
Fan
Ke
K
Shuai
D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002843:Chromatin / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006657:Histones / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011401:Promoter Regions, Genetic; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D000097584:DNA Methyltransferase 3B
D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051858:Forkhead Transcription Factors; D006657:Histones; D050828:Protein Inhibitors of Activated STAT; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; D000097584:DNA Methyltransferase 3B; C498833:Foxp3 protein, mouse; C494211:Pias1 protein, mouse