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Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells.

Authors
 Joo-Hong Park  ;  Yeeun Choi  ;  Min-Ji Song  ;  Keunhee Park  ;  Jong-Joo Lee  ;  Hyoung-Pyo Kim 
Citation
 JOURNAL OF IMMUNOLOGY, Vol.196(10) : 4378-4389, 2016 
Journal Title
JOURNAL OF IMMUNOLOGY
ISSN
 0022-1767 
Issue Date
2016
MeSH
Animals ; Base Sequence ; CCCTC-Binding Factor ; CD4-Positive T-Lymphocytes/metabolism* ; Cell Cycle Proteins/metabolism ; Chromatin/genetics* ; Chromosomal Proteins, Non-Histone/metabolism ; Conserved Sequence ; DNA-Binding Proteins/genetics* ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Humans ; Interleukin-6/pharmacology ; Interleukins/genetics* ; Mice ; Mice, Inbred C57BL ; NFATC Transcription Factors/metabolism ; Promoter Regions, Genetic ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction
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.
Full Text
http://www.jimmunol.org/content/196/10/4378
DOI
10.4049/jimmunol.1500636
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Environmental Medical Biology (환경의생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyoung Pyo(김형표) ORCID logo https://orcid.org/0000-0003-1441-8822
Song, Min Ji(송민지)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146834
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