CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus.
How cell type-specific differences in chromatin conformation are achieved and their contribution to gene expression are incompletely understood. Here we identify a cryptic upstream orchestrator of interferon-gamma (IFNG) transcription, which is embedded within the human IL26 gene, compromised of a single CCCTC-binding factor (CTCF) binding site and retained in all mammals, even surviving near-complete evolutionary deletion of the equivalent gene encoding IL-26 in rodents. CTCF and cohesins occupy this element in vivo in a cell type-nonspecific manner. This element is juxtaposed to two other sites located within the first intron and downstream of Ifng, where CTCF, cohesins, and the transcription factor T-bet bind in a T helper 1 (Th1) cell-specific manner. These interactions, close proximity of other elements within the locus to each other and to the gene encoding interferon-gamma, and robust murine Ifng expression are dependent on CTCF and T-bet. The results demonstrate that cooperation between architectural (CTCF) and transcriptional enhancing (T-bet) factors and the elements to which they bind is required for proper Th1 cell-specific expression of Ifng.
Sekimata
Masayuki
M
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Pérez-Melgosa
Mercedes
M
Miller
Sara A
SA
Weinmann
Amy S
AS
Sabo
Peter J
PJ
Sandstrom
Richard
R
Dorschner
Michael O
MO
Stamatoyannopoulos
John A
JA
Wilson
Christopher B
CB
D000818:Animals; D000076246:CCCTC-Binding Factor; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007438:Introns / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D000097722:Cohesins; D000098815:T-bet Transcription Factor
D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D007371:Interferon-gamma; D007378:Interleukins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000097722:Cohesins; D000098815:T-bet Transcription Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; C406767:IL26 protein, human