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Molecular and Cellular Biology, December 2007, p. 8510-8521, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01615-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

T-bet's Ability To Regulate Individual Target Genes Requires the Conserved T-Box Domain To Recruit Histone Methyltransferase Activity and a Separate Family Member-Specific Transactivation Domain{triangledown}

Megan D. Lewis,1 Sara A. Miller,2 Michael M. Miazgowicz,1 Kristin M. Beima,1 and Amy S. Weinmann1*

Department of Immunology,1 Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 981952

Received 31 August 2007/ Accepted 30 September 2007

Appropriate cellular differentiation and specification rely upon the ability of key developmental transcription factors to precisely establish gene expression patterns. These transcription factors often regulate epigenetic events. However, it has been unclear whether this is the only role that they play in functionally regulating developmental gene expression pathways or whether they also participate in downstream transactivation events at the same promoter. The T-box transcription factor family is important in cellular specification events in many developmental systems, and determining the molecular mechanisms by which this family regulates gene expression networks warrants attention. Here, we examine the mechanism by which T-bet, a critical T-box protein in the immune system, influences transcription. T-bet is both necessary and sufficient to induce permissive histone H3-K4 dimethyl modifications at the CXCR3 and IFN-{gamma} promoters. A T-bet structure-function analysis revealed that the conserved T-box domain, with a small C-terminal portion, is required for recruiting histone methyltransferase activity to promoters. Interestingly, this function is conserved in the T-box family and is necessary, but not sufficient, to induce transcription, with an independent transactivation activity also required. The requirement for two separable functional activities may ultimately contribute to the stringent role for T-box proteins in establishing specific developmental gene expression pathways.

* Corresponding author. Mailing address: Department of Immunology, University of Washington, Box 357650, 1959 NE Pacific St., Seattle, WA 98195. Phone: (206) 616-7235. Fax: (206) 543-1013. E-mail: weinmann{at}u.washington.edu

{triangledown} Published ahead of print on 8 October 2007.

Molecular and Cellular Biology, December 2007, p. 8510-8521, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01615-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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