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PMID: 17938200 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells.

Molecular and cellular biology ·Vol. 27 ·No. 24 ·2007-12-00 ·Pages 8815-23

Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM

Abstract

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.

MeSH Terms
Animals Cyclins/deficiency Epithelial Cells/enzymology,metabolism Gene Expression Regulation HeLa Cells Humans Mice Positive Transcriptional Elongation Factor B/metabolism Promoter Regions, Genetic/genetics RNA Polymerase II/metabolism RNA-Binding Proteins/metabolism Thymus Gland/cytology,enzymology,metabolism Transcription Factors/metabolism Transcription, Genetic Transcriptional Activation
Chemicals
APECED protein Cyclins RNA-Binding Proteins Transcription Factors Positive Transcriptional Elongation Factor B RNA Polymerase II
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Oven Irena
Department of Medicine, Rosalind Russell Medical Research Center, University of California-San Francisco, San Francisco, California 94143-0703, USA.
Brdicková Nadezda
Kohoutek Jiri
Vaupotic Tomaz
Narat Mojca
Peterlin B Matija
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01085-07
Published
2007-12-00
Epub
2007-00-15
Pages
8815-23
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2169392
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.01085-07 PMC Full Text View journal details
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