YB-1 and CTCF Differentially Regulate the 5-HTT Polymorphic Intron 2 Enhancer Which Predisposes to a Variety of Neurological Disorders

Klenova, Elena; Scott, A C; Roberts, Julian; Shamsuddin, Shaharum; Lovejoy, Elizabeth A.; Bergmann, Stephan; Bubb, Vivien J.; Royer, Hans-Dieter; Quinn, John P.

doi:10.1523/jneurosci.1150-04.2004

Cited by 79 publications

(83 citation statements)

References 46 publications

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“…In addition to VNTR copy number, the different primary DNA sequence of the VNTR elements that constitute the VNTR can support differential reporter gene expression (Lovejoy et al, 2003). Our most recent report has demonstrated that the SLC6A4 intron 2 VNTR is bound and regulated by the transcription factor Y-box binding protein 1 (YB-1) (Klenova et al, 2004) a member of the Y-box binding proteins (Wolffe et al, 1992;Wolffe, 1994;Swamynathan et al, 2002;Kohno et al, 2003), and this regulation is modulated by the transcription factor CCCTC binding protein (CTCF) (Klenova et al, 2004), a known binding partner of YB-1 (Chernukhin et al, 2000). CTCF, in addition to transcriptional activation or silencing in a context-dependent manner, organizes epigenetically controlled chromatin insulators regulating imprinted genes (Klenova et al, 1993;Filippova et al, 1996;Ohlsson et al, 2001;Klenova et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Roberts

Scott²,

Howard³

et al. 2007

J. Neurosci.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Roberts

Scott²,

Howard³

et al. 2007

J. Neurosci.

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“…Thus, CTCF interactions with Sin3 (37) and YB-1 (10,28) are shown to modulate CTCF function as a transcriptional repressor. The cooperation of CTCF with nucleophosmin (68), Kaiso (13), and helicase protein CHD8 (22) has been linked to the control of insulator function of CTCF and epigenetic regulation.…”

mentioning

confidence: 99%

CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide

Chernukhin

Shamsuddin

Kang

et al. 2007

Molecular and Cellular Biology

154

130

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CTCF is a transcription factor with highly versatile functions ranging from gene activation and repression to the regulation of insulator function and imprinting. Although many of these functions rely on CTCF-DNA interactions, it is an emerging realization that CTCF-dependent molecular processes involve CTCF interactions with other proteins. In this study, we report the association of a subpopulation of CTCF with the RNA polymerase II (Pol II) protein complex. We identified the largest subunit of Pol II (LS Pol II) as a protein significantly colocalizing with CTCF in the nucleus and specifically interacting with CTCF in vivo and in vitro. The role of CTCF as a link between DNA and LS Pol II has been reinforced by the observation that the association of LS Pol II with CTCF target sites in vivo depends on intact CTCF binding sequences. “Serial” chromatin immunoprecipitation (ChIP) analysis revealed that both CTCF and LS Pol II were present at the β-globin insulator in proliferating HD3 cells but not in differentiated globin synthesizing HD3 cells. Further, a single wild-type CTCF target site (N-Myc-CTCF), but not the mutant site deficient for CTCF binding, was sufficient to activate the transcription from the promoterless reporter gene in stably transfected cells. Finally, a ChIP-on-ChIP hybridization assay using microarrays of a library of CTCF target sites revealed that many intergenic CTCF target sequences interacted with both CTCF and LS Pol II. We discuss the possible implications of our observations with respect to plausible mechanisms of transcriptional regulation via a CTCF-mediated direct link of LS Pol II to the DNA.

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“…For example, the minisatellite located in intron 2 of the serotonin transporter gene 5-HTT may influence its transcription levels by binding the transcription factor YB-1 (Klenova et al, 2004). The location of minisatellites involved in the regulation of gene expression and function need not be limited to promoter sequences.…”

Section: Minisatellite Loci In Human Dnamentioning

confidence: 99%

Minisatellite DNA Markers in Population Studies

Limborska¹,

Khrunin²,

Verbenko³

2012

Studies in Population Genetics

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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 associ-

Cited by 79 publications

References 46 publications

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

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

CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide

Minisatellite DNA Markers in Population Studies

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