A distal conserved sequence element controls Ifng gene expression by T cells and NK cells.
Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.
Hatton
Robin D
RD
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Harrington
Laurie E
LE
Luther
Rita J
RJ
Wakefield
Therese
T
Janowski
Karen M
KM
Oliver
James R
JR
Lallone
Roger L
RL
Murphy
Kenneth M
KM
Weaver
Casey T
CT
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002454:Cell Differentiation / Q000276:immunology; D002645:Chickens; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics*; D015870:Gene Expression / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009893:Opossums; D016133:Polymerase Chain Reaction; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D006657:Histones; D007371:Interferon-gamma