title: The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model.
abstract: Functional short tandem repeats (STR) are polymorphic in the population, and the number of repeats regulates the expression of nearby genes (known as expression STR, eSTR). STR in IGF1 promoter has been extensively studied for its association with IGF1 concentration in blood and various clinical traits and represents an important eSTR. We previously used an in-vitro luciferase reporter model to examine the interaction between STRs and SNPs in IGF1 promoter. Here, we further explored the mechanism how the number of repeats of the STR regulates gene transcription. An inverse correlation between the number of repeats and the extent of transactivation was found in a haplotype consisting of three promoter SNPs (C-STR-T-T). We showed that these adjacent SNPs located outside the STR were required for the STR to function as eSTR. The C allele of rs35767 provides a binding site for CCAAT/enhancer-binding-protein δ (C/EBPD), which is essential for the gradational transactivation property of eSTR and FOXA3 may also be involved. Therefore, we propose a mechanism in which the gradational transactivation by the eSTR is caused by the interaction of one or more transcriptional complexes located outside the STR, rather than by direct binding to a repeat motif of the STR.
authors.affiliation: Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Holly Y
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Suk Ling
authors.initials: SL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, China.
authors.forename: Lindan
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Vincent H K
authors.initials: VH
authors.lastname: Leung
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
authors.forename: Honglin
authors.initials: H
authors.lastname: Jiang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Laboratory of Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.|Functional Genomics and Biostatistical Computing laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, China.|KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, China.
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Tang
mesh_terms: D002460:Cell Line; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics*; D059372:Nucleotide Motifs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I