Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF.
Two distinct variable number tandem repeats (VNTRs) within the human serotonin transporter gene (SLC6A4) have been implicated as predisposing factors for CNS disorders. The linked polymorphic region in the 5'-promoter exists as short (s) and long (l) alleles of a 22 or 23 bp elements. The second within intron 2 (Stin2) exists as three variants containing 9, 10 or 12 copies of a 16 or 17 bp element. These VNTRs, individually or in combination, supported differential reporter gene expression in rat neonate prefrontal cortical cultures. The level of reporter gene activity from the dual VNTR constructs indicated combinatorial action between the two domains. Chromatin immunoprecipitation demonstrated that both these VNTR domains can bind the CCCTC-binding factor and this correlated with the ability of exogenously supplied CCCTC-binding factor to modulate the expression supported by these reporter gene constructs. We suggest that the potential for interaction between multiple polymorphic domains should be incorporated into genetic association studies.
School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
Fahad R
FR
Ali
Sylvia A
SA
Vasiliou
Kate
K
Haddley
Ursula M
UM
Paredes
Julian C
JC
Roberts
Fabio
F
Miyajima
Elena
E
Klenova
Vivien J
VJ
Bubb
John P
JP
Quinn
D000818:Animals; D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D014644:Genetic Variation / Q000502:physiology*; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats / Q000502:physiology*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins