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The Journal of Neuroscience, March 14, 2007, 27(11):2793-2801; doi:10.1523/JNEUROSCI.0892-06.2007
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Cellular/Molecular
Differential Regulation of the Serotonin Transporter Gene by Lithium Is Mediated by Transcription Factors, CCCTC Binding Protein and Y-Box Binding Protein 1, through the Polymorphic Intron 2 Variable Number Tandem Repeat
Julian Roberts,1,2,3 * Alison C. Scott,1,2 * Mark R. Howard,1,2 Gerome Breen,4 Vivien J. Bubb,2,3 Elena Klenova,5 andJohn P. Quinn1,2 1Physiology Laboratory, School of Biomedical Science, 2Department of Human Anatomy and Cell Biology, School of Biomedical Science, and 3Neurological Science, Medical School, University of Liverpool, Liverpool L69 3BX, United Kingdom, 4Medical Research Council Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom, and 5Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, United Kingdom
Correspondence should be addressed to either of the following: Elena Klenova, Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK, Email: klenovae{at}essex.ac.uk; or John P. Quinn, Physiology Laboratory, School of Biomedical Science, University of Liverpool, Liverpool L69 3BX, UK, Email: jquinn{at}liv.ac.uk
The serotoninergic pathways are possible targets for the action of lithium, a therapeutic agent for treatment of bipolar affective disorders. This study aimed to investigate the molecular mechanisms regulating human serotonin transporter gene (SLC6A4) expression by lithium and, specifically, the role of the variable number tandem repeat (VNTR) polymorphic region in intron 2, which is potentially a predisposing genetic factor for bipolar affective disorders. We demonstrated that addition of lithium to human JAr cells led to changes in the levels of SLC6A4 mRNA and protein. Additional investigations revealed that the intron 2 VNTR domain was a potential target for mediation of a transcriptional response to lithium. Properties of two transcription factors, CCCTC binding protein (CTCF) and Y-box binding protein 1 (YB-1), previously shown to be involved in the regulation of SLC6A4 VNTR, were found to be modulated by LiCl. Thus, levels of CTCF and YB-1 mRNA and protein were altered in vivo in response to LiCl. Furthermore, CTCF and YB-1 showed differential binding to the polymorphic alleles of the VNTR on exposure to LiCl. Our data suggest a model in which differential binding of CTCF and YB-1 to the allelic variants of the intron 2 VNTR can be regulated by lithium and in part result in differential and even aberrant expression of SLC6A4. Our study of the regulation of the SLC6A4 VNTR by lithium may improve the understanding of psychiatric disorders and enable the development of novel therapies for conditions such as bipolar affective disorder to target only the at-risk allele.
Key words: CTCF; YB-1; SLC6A4; VNTR; affective disorders; transcription; lithium
Received Aug. 23, 2005; revised Jan. 29, 2007; accepted Jan. 30, 2007.
Correspondence should be addressed to either of the following: Elena Klenova, Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK, Email: klenovae{at}essex.ac.uk; or John P. Quinn, Physiology Laboratory, School of Biomedical Science, University of Liverpool, Liverpool L69 3BX, UK, Email: jquinn{at}liv.ac.uk
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