The gene encoding the fragile X RNA-binding protein is controlled by nuclear respiratory factor 2 and the CREB family of transcription factors.
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.
Smith
Karen T
KT
Program in Genetics & Molecular Biology and Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
Nicholls
Robert D
RD
Reines
Daniel
D
D051696:Activating Transcription Factors / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D051720:Upstream Stimulatory Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D051696:Activating Transcription Factors; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D051268:GA-Binding Protein Transcription Factor; D012097:Repressor Proteins; D051720:Upstream Stimulatory Factors; D050880:p300-CBP Transcription Factors; C497683:FMR1 protein, human