YB-1 and CTCF differentially regulate the 5-HTT polymorphic intron 2 enhancer which predisposes to a variety of neurological disorders.

Abstract	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.
Authors	Elena Klenova, Alison C Scott, Julian Roberts, Shaharum Shamsuddin, Elizabeth A Lovejoy, Stephan Bergmann, Vivien J Bubb, Hans-Dieter Royer, John P Quinn
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 24 Issue 26 Pg. 5966-73 (Jun 30 2004) ISSN: 1529-2401 [Electronic] United States
PMID	15229244 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CCCTC-Binding Factor CTCF protein, human DNA, Complementary DNA-Binding Proteins Membrane Glycoproteins Membrane Transport Proteins Nerve Tissue Proteins Nuclear Proteins Recombinant Fusion Proteins Repressor Proteins SLC6A4 protein, human Serotonin Plasma Membrane Transport Proteins Transcription Factors Y-Box-Binding Protein 1 YBX1 protein, human
Topics	Alleles Animals Binding Sites CCCTC-Binding Factor COS Cells Cell Line Chickens Chlorocebus aethiops DNA, Complementary (genetics) DNA-Binding Proteins (physiology) Gene Expression Regulation (physiology) Genes, Reporter Humans Introns (genetics) Kidney Membrane Glycoproteins (biosynthesis, genetics) Membrane Transport Proteins (biosynthesis, genetics) Minisatellite Repeats Mood Disorders (genetics, metabolism) Nerve Tissue Proteins (biosynthesis, genetics) Nuclear Proteins Polymorphism, Genetic Protein Binding (drug effects) Protein Interaction Mapping Protein Structure, Tertiary Recombinant Fusion Proteins (metabolism) Repressor Proteins (physiology) Serotonin Plasma Membrane Transport Proteins Transcription Factors (physiology) Transcription, Genetic Transfection Two-Hybrid System Techniques Y-Box-Binding Protein 1 Zinc Fingers

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