Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 6, Pages 2034-2039Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0409510102
Keywords
corepressor; DNA methylation; transcription
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Funding
- NCI NIH HHS [CA68485, P30 CA068485] Funding Source: Medline
- NIAID NIH HHS [R01 AI049460, R21 AI049460] Funding Source: Medline
- NIDDK NIH HHS [P30 DK020593, DK20593, P60 DK020593] Funding Source: Medline
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Promoter DNA methylation is a major epigenetic mechanism for silencing genes and establishing commitment in cells differentiating from their precursors. The transcription factor T-bet is a key determinant of IFN-gamma gene expression in helper T cells, but the mechanisms by which it achieves this effect are not clear. It is shown here that T-bet binds to a highly conserved T-box half-site in the IFN-gamma promoter, is recruited to the endogenous IFN-gamma promoter in T lymphoid cells, and transactivates gene expression through this sequence in a manner dependent on consensus T-box residues. This conserved promoter site is methylated in a model T cell line, and enforced T-bet expression did not alter its complete methylation. T-bet transactivated the conserved core promoter in transfection assays and collaborated functionally with C/EBPbeta despite methylation of the conserved element. Importantly, enforced T-bet expression led to dissociation of the mSin3a corepressor from the endogenous, chromatinized IFN-gamma promoter without decreasing loading of the methyl-CpG binding protein MeCP2. These data indicate that T-bet can override repressive epigenetic modification by a mechanism in which this master regulator acts through a T-box half-site to enforce the activation of IFN-gamma gene expression in part by decreased loading of a corepressor on methylated DNA.
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