Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.
The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1A C(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1A receptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1A receptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108-15 cells), Deaf-1 enhanced 5-HT1A promoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.
Ottawa Health Research Institute (Neuroscience), Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Canada.
Margaret
M
Czesak
Sylvie
S
Lemonde
Erica A
EA
Peterson
Anastasia
A
Rogaeva
Paul R
PR
Albert
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D019964:Mood Disorders / Q000235:genetics; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000502:physiology*; D011110:Polymorphism, Genetic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D014157:Transcription Factors; D014162:Transfection
C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D044282:Receptor, Serotonin, 5-HT1A