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Nucleic Acids Research 2005 33(21):6850-6860; doi:10.1093/nar/gki989
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Published online 2 December 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

CTCF binds the proximal exonic region of hTERT and inhibits its transcription

Stéphanie Renaud, Dmitri Loukinov1, Fred T. Bosman, Victor Lobanenkov1 and Jean Benhattar*

Institute of Pathology, Centre Hospitalier Universitaire Vaudois Bugnon 25, 1011 Lausanne, Switzerland 1Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health Rockville, MD 20892, USA

*To whom correspondence should be addressed. Tel: +41 21 314 7153; Fax: +41 21 314 7115; Email: Jean.Benhattar{at}chuv.hospvd.ch

Received March 24, 2005. Revised June 16, 2005. Accepted November 14, 2005.

The expression of the catalytic subunit (hTERT) represents the limiting factor for telomerase activity. Previously, we detected a transcriptional repressor effect of the proximal exonic region (first two exons) of the hTERT gene. To better understand the mechanism involved and to identify a potential repressor, we further characterized this region. The addition of the hTERT proximal exonic region downstream of the hTERT minimal promoter strongly reduced promoter transcriptional activity in all cells tested (tumor, normal and immortalized). This exonic region also significantly inhibited the transcriptional activity of the CMV and CDKN2A promoters, regardless of the cell type. Therefore, the repressor effect of hTERT exonic region is neither cell nor promoter-dependent. However, the distance between the promoter and the exonic region can modulate this repressor effect, suggesting that nucleosome positioning plays a role in transcriptional repression. We showed by electrophoretic mobility shift assay that CCCTC-binding factor (CTCF) binds to the proximal exonic region of hTERT. Chromatin immunoprecipitaion assays confirmed the binding of CTCF to this region. CTCF is bound to hTERT in cells in which hTERT is not expressed, but not in telomerase-positive ones. Moreover, the transcriptional downregulation of CTCF by RNA interference derepressed hTERT gene expression in normal telomerase-negative cells. Our results suggest that CTCF participates in key cellular mechanisms underlying immortality by regulating hTERT gene expression.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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