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

Abstract

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.

Microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene is associated with susceptibility to acute pancreatitis in Japan

“…It remains unknown whether the impact of an S allele in combination with an L allele equals that of two M alleles. Of note, for other genes with variable numbers of tandem repeats, it has been demonstrated that length variation in the number of repeats can influence transcription [34,35]. A good example is an association of various numbers of tandem repeats in the regulatory region of SMYD3 with various cancers including colorectal cancer, hepatocellular carcinoma, and breast cancer [34].…”

A putative amino acid transporter of the solute carrier 6 family is upregulated by lithium and is required for resistance to lithium toxicity in Drosophila

“…In the case of transcriptional mechanisms, for example, it may be necessary to test the intronic sequences of List for their potential regulatory function. Indeed, a recent report has demonstrated that expression of the human serotonin transporter gene (SLC6A4) is regulated by lithium through transcription factors that bind to the variable number tandem repeat (VNTR) polymorphic region in the second intron of the gene (Roberts et al, 2007). …”

From Genes to Animal Behavior

“…Later in life, personality develops in predictable ways: mean trait levels of neuroticism decrease, agreeableness and conscientiousness increase, and openness first increases and then decreases during adult life (Roberts et al 2006). Caspi et al 2005;Roberts et al 2007). Stamps 2003).…”

“…In humans, personality is understood as a psychological construct that influences behavior and is organized in a hierarchical structure (Maltby et al 2007; see also, e.g., Allport 1961 (Bouchard and Loehlin 2001) and associated with important life outcomes, such as subjective well-being, health, mortality, mating success, quality of social relationships, occupational performance, psychopathology, and the likelihood of serious injuries (Franken et al 1990;Neeleman et al 2002;Nettle 2005;Ozer and Benet-Martinez 2006;Roberts et al 2007). The aim is to understand similarities and differences in human and animal personality regarding the structure, underlying neuropsychological mechanisms, and evolutionary history.…”