The serotonin transporter (5-HTT) gene contains a variable number tandem repeat 
(VNTR) domain within intron 2 that is often associated with a number of 
neurological conditions, including affective disorders. The implications of this 
polymorphism are not yet understood, however, we have previously demonstrated 
that the 5-HTT VNTR is a transcriptional regulatory domain, and the allelic 
variation supports differential reporter gene expression in vivo and in vitro. 
The aim of this study was to identify transcription factors responsible for the 
regulation of this VNTR. Using a yeast one-hybrid screen, we found the 
transcription factor Y box binding protein 1 (YB-1) interacts with the 5-HTT 
VNTR. Consistent with this, we demonstrate in a reporter gene assay that the 
polymorphic VNTR domains differentially respond to exogenous YB-1 and that YB-1 
will bind to the VNTR in vitro in a sequence-specific manner. Interestingly, the 
transcription factor CCTC-binding factor (CTCF), previously shown to interact 
with YB-1, interferes with the ability of the VNTR to support YB-1-directed 
reporter gene expression. In addition, CTCF blocks the binding of YB-1 to its 
DNA recognition sequences in vitro, thus providing a possible mechanism of 
regulation of YB-1 activation of the VNTR by CTCF. Therefore, we have identified 
YB-1 and CTCF as transcription factors responsible, at least in part, for 
modulation of VNTR function as a transcriptional regulatory domain. Our data 
suggest a novel mechanism that explains, in part, the ability of the distinct 
VNTR copy numbers to support differential reporter gene expression based on YB-1 
binding sites.