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Nucleic Acids Research 2006 34(4):1205-1215; doi:10.1093/nar/gkj521
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Published online 25 February 2006

© The Author 2006. 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

The gene encoding the fragile X RNA-binding protein is controlled by nuclear respiratory factor 2 and the CREB family of transcription factors

Karen T. Smith, Robert D. Nicholls1 and Daniel Reines*

Program in Genetics & Molecular Biology and Department of Biochemistry, Emory University School of Medicine 1510 Clifton Road, Atlanta, GA 30322, USA 1Birth Defects Laboratories and Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh 3705 Fifth Avenue, Pittsburgh, PA 15213, USA

*To whom correspondence should be addressed. Tel: +1 404 727 3361; Fax: +1 404 727 3452; Email: dreines{at}emory.edu

Received November 15, 2005. Revised January 18, 2006. Accepted February 7, 2006.

FMR1 encodes an RNA-binding protein whose absence results in fragile X mental retardation. In most patients, the FMR1 gene is cytosine-methylated and transcriptionally inactive. NRF-1 and Sp1 are known to bind and stimulate the active, but not the methylated/silenced, FMR1 promoter. Prior analysis has implicated a CRE site in regulation of FMR1 in neural cells but the role of this site is controversial. We now show that a phospho-CREB/ATF family member is bound to this site in vivo. We also find that the histone acetyltransferases CBP and p300 are associated with active FMR1 but are lost at the hypoacetylated fragile X allele. Surprisingly, FMR1 is not cAMP-inducible and resides in a newly recognized subclass of CREB-regulated genes. We have also elucidated a role for NRF-2 as a regulator of FMR1 in vivo through a previously unrecognized and highly conserved recognition site in FMR1. NRF-1 and NRF-2 act additively while NRF-2 synergizes with CREB/ATF at FMR1's promoter. These data add FMR1 to the collection of genes controlled by both NRF-1 and NRF-2 and disfavor its membership in the immediate early response group of genes.


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