Identification and characterization of the Hesr1/Hey1 as a candidate trans-acting factor on gene expression through the 3' non-coding polymorphic region of the human dopamine transporter (DAT1) gene.
Expression of the dopamine transporter (DAT) gene affects dopaminergic neurotransmission. A variable number tandem repeat (VNTR) polymorphism in the 3' non-coding region of the human DAT (DAT1) gene has been reported to affect gene expression as a cis-element, and is associated with some neuropsychiatric disorders. In this study, we identified the basic helix-loop-helix (bHLH) transcriptional factor Hesr1 (the Hairy/enhancer of split related transcriptional factor 1 with a YRPW motif, also named Hey1/HERP2/HRT1/CHF2) as a trans-acting factor in a yeast one-hybrid system, and showed that Hesr1 down-regulates reporter gene expression with the 3' non-coding region of DAT1 gene in mammalian cell lines. The negative regulations depend on bHLH and the Orange domain of the molecule, but not the YRPW motif. The negative regulations affect the VNTR-dependent differences in gene expression. In addition, we identified a splice variant, Hesr1-12nt, with a lower activity. We also show that SNP of Hesr1, C386A, causes a lack of activity. These results suggest that Hesr1 and its polymorphism(s) might be involved in dopamine-related polygenic disorders and behavioral traits.
Fuke
Satoshi
S
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902.
Sasagawa
Noboru
N
Ishiura
Shoichi
S
D024509:3' Flanking Region; D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D050483:Dopamine Plasma Membrane Transport Proteins; D015536:Down-Regulation; D015870:Gene Expression; D005787:Gene Frequency; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D018598:Minisatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C485631:HEY1 protein, human; C493214:SLC6A3 protein, human