A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells

Robin D. Hatton, Laurie E. Harrington, Rita J. Luther, Therese Wakefield, Karen M. Janowski, James R. Oliver, Roger L. Lallone, Kenneth M. Murphy, Casey T. Weaver

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)717-729
Number of pages13
JournalImmunity
Volume25
Issue number5
DOIs
StatePublished - Nov 2006

Keywords

  • CELLIMMUNO
  • DNA

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