title: Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells.
abstract: IL-21, a pleiotropic cytokine strongly linked with autoimmunity and inflammation, regulates diverse immune responses. IL-21 can be potently induced in CD4(+) T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il21 gene at the chromatin level. In this study, we demonstrated that a conserved noncoding sequence located 49 kb upstream of the Il21 gene contains an enhancer element that can upregulate Il21 gene expression in a STAT3- and NFAT-dependent manner. Additionally, we identified enhancer-blocking insulator elements in the Il21 locus, which constitutively bind CTCF and cohesin. In naive CD4(+) T cells, these upstream and downstream CTCF binding sites interact with each other to make a DNA loop; however, the Il21 promoter does not interact with any cis-elements in the Il21 locus. In contrast, stimulation of CD4(+) T cells with IL-6 leads to recruitment of STAT3 to the promoter and novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity. The long-range interaction between the promoter and distal enhancer region was dependent on IL-6/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of the Il21 gene.
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
authors.forename: Joo-Hong
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Yeeun
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Song
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jong-Joo
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Environmental Medical Biology, Yonsei University College of Medicine, Seoul 120-752, Korea; Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea kimhp@yuhs.ac.
authors.forename: Hyoung-Pyo
authors.initials: HP
authors.lastname: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000097722:Cohesins; D000098546:Interleukin-21
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007378:Interleukins; D050778:NFATC Transcription Factors; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000097722:Cohesins; D000098546:Interleukin-21; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; C494007:Nfatc2 protein, mouse; C494087:Stat3 protein, mouse