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Molecular and Cellular Biology, December 2007, p. 8815-8823, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01085-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells ^,

Irena Oven,^1,2, Nadda Brdiková,^1, Jiri Kohoutek,^1, Toma Vaupoti,³ Mojca Narat,² and B. Matija Peterlin^1*

Departments of Medicine, Microbiology and Immunology, Rosalind Russell Medical Research Center, University of California—San Francisco, San Francisco, California 94143-0703,¹ Department of Animal Science, Biotechnical Faculty, University of Ljubljana, SI-1230 Domzale, Slovenia,² Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia³

Received 19 June 2007/ Returned for modification 17 August 2007/ Accepted 2 October 2007

AIRE is a transcriptional activator that directs the ectopic expression of many tissue-specific genes in medullary thymic epithelial cells, which plays an important role in the negative selection of autoreactive T cells. However, its mechanism of action remains poorly understood. In this study, we found that AIRE regulates the step of elongation rather than initiation of RNA polymerase II. For these effects, AIRE bound and recruited P-TEFb to target promoters in medullary thymic epithelial cells. In these cells, AIRE activated the ectopic transcription of insulin and salivary protein 1 genes. Indeed, by chromatin immunoprecipitation, we found that RNA polymerase II was already engaged on these promoters but was unable to elongate in the absence of AIRE. Moreover, the genetic inactivation of cyclin T1 from P-TEFb abolished the transcription of AIRE-responsive genes and led to lymphocytic infiltration of lacrimal and salivary glands in the CycT1^–/– mouse. Our findings reveal critical steps by which AIRE regulates the transcription of genes that control central tolerance in the thymus.

Published ahead of print on 15 October 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally.