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Cell type‐dependent recruitment of trichostatin A‐sensitive repression of the human 5‐HT1A receptor gene
Author(s) -
Lemonde Sylvie,
Rogaeva Anastasia,
Albert Paul R.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02223.x
Subject(s) - psychological repression , repressor , trichostatin a , biology , histone deacetylase , gene silencing , regulation of gene expression , microbiology and biotechnology , gene , gene expression , genetics , histone
Regulation of serotonin (5‐HT)1A receptor expression in brain is implicated in mood disorders such as depression and anxiety. Transcriptional activity of the human 5‐HT1A receptor gene was strongly repressed by a negative regulatory region containing a consensus repressor element‐1 (RE‐1) and two copies of the dual repressor element (DRE) identified in the rat 5‐HT1A receptor gene. REST/NRSF, a silencer of neuronal genes, bound the 5‐HT1A RE‐1 and repressed the 5‐HT1A promoter. Inactivation of RE‐1 completely abolished REST‐mediated repression, but resulted in only partial (15–50%) de‐repression of basal 5‐HT1A promoter activity. The human 5‐HT1A DRE sequences bound specifically to the novel repressor Freud‐1 (5′repressor element under dual repression binding protein‐1) and conferred repressor activity at 5‐HT1A or SV40 promoters. In 5‐HT1A‐negative cells [L6, human embryonic kidney (HEK) 293], the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) abolished repression mediated by both RE‐1/REST and DRE/Freud‐1, and induced almost complete de‐repression of the 5‐HT1A gene. By contrast, in 5‐HT1A‐expressing neuronal cells (RN46A, SN‐48) TSA blocked RE‐1/REST repression, but did not affect DRE/Freud‐1‐mediated repression. Thus in contrast to REST, Freud‐1 mediates HDAC‐independent repression of the 5‐HT1A receptor promoter in neuronal 5‐HT1A‐positive cells, suggesting that HDAC recruitment might influence neuron‐specific gene expression by further silencing expression in non‐neuronal tissue.