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 clust...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2006-11, Vol.25 (5), p.717-729
Main Authors: Hatton, Robin D., Harrington, Laurie E., Luther, Rita J., Wakefield, Therese, Janowski, Karen M., Oliver, James R., Lallone, Roger L., Murphy, Kenneth M., Weaver, Casey T.
Format: Article
Language:English
Subjects:
Animals
Artificial chromosomes
Base Sequence
Cattle
Cell Differentiation - immunology
CELLIMMUNO
Chickens
Chromatin
Chromosomes, Artificial, Bacterial - genetics
Conserved Sequence - genetics
Deoxyribonucleic acid
DNA
Epigenetics
Gene expression
Gene Expression - immunology
Gene Expression Regulation - immunology
Histones - metabolism
Interferon-gamma - genetics
Killer Cells, Natural - immunology
Lymphocytes
Mice
Mice, Transgenic
Molecular Sequence Data
Opossums
Polymerase Chain Reaction
Rats
Regulatory Elements, Transcriptional - immunology
T-Lymphocytes - cytology
T-Lymphocytes - immunology
Transcription factors
Variance analysis
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Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2006.09.007