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Journal of Biochemistry 2005 137(2):205-216; doi:10.1093/jb/mvi020
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© 2005 The Japanese Biochemical Society

BIOCHEMISTRY

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

Satoshi Fuke, Noboru Sasagawa and Shoichi Ishiura1

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902

1 To whom correspondence should be addressed. Tel/Fax: +81-3-5454-6739, E-mail: cishiura{at}mail.ecc.u-tokyo.ac.jp

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.


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