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The mental retardation gene CC2D1A/Freud‐1 encodes a long isoform that binds conserved DNA elements to repress gene transcription
Author(s) -
Rogaeva Anastasia,
Albert Paul R.
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05727.x
Subject(s) - gene isoform , biology , repressor , chromatin , nuclear receptor , nuclear receptor co repressor 1 , microbiology and biotechnology , gene , transcription (linguistics) , regulation of gene expression , psychological repression , chromatin immunoprecipitation , gene expression , genetics , promoter , transcription factor , linguistics , philosophy
The CC2D1A / Freud‐1 gene has recently been linked to non‐syndromic mental retardation and a short isoform of mouse Five prime REpressor Under Dual repression binding protein 1 (Freud‐1) can repress the serotonin‐1A (5‐HT1A) receptor gene in rodent cells. In this study, we addressed the expression, localization and regulation of the human 5‐HT1A receptor gene by a long isoform of human Freud‐1 protein (Freud‐1 L ). We show that human CC2D1A/Freud‐1 RNA is expressed in brain and peripheral tissues and encodes short and long isoforms, which differ by an upstream in‐frame translational start site. Whereas previous studies identified the short isoform of Freud‐1 as the predominant isoform in rodent cells, we demonstrate that the long isoform is more abundant in human cells, especially in the nuclear fraction. The nuclear localization of Freud‐1 L was enriched upon inhibition of chromosome region maintenance 1/exportin 1‐dependent nuclear export, indicating a dynamic regulation of Freud‐1 nuclear localization. Consistent with a functional role in the nucleus, human Freud‐1 L bound specifically to its dual repressor element in the 5‐HT1A receptor gene in vitro and repressed transcription from these sites. Importantly, chromatin immunoprecipitation using antibodies specific for human Freud‐1 L demonstrated that it is bound to the dual repressor element in chromatin, indicating a functional role in regulating the basal expression of the 5‐HT1A receptor gene. Taken together, these results indicate that both the short and long isoforms of Freud‐1 are expressed, although Freud‐1 L is the major isoform that regulates the human 5‐HT1A receptor gene. Disruption of transcriptional regulation by mutation of Freud‐1 may play a role in abnormal brain function leading to mental retardation.