Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes.
The biological mechanism of a recent discovered association of type 2 diabetes with the ACAA-insertion/deletion polymorphism at the 3'UTR of the IGF2R gene has remained unclear. A very recently emerging novel polymorphic control layer by microRNAs (miRNAs) makes it possible to elucidate this issue. In this study, a prediction by web tools MicroInspector and miRanda demonstrated that DNA sequence polymorphism (DSPs) ACAA-insertion/deletion in IGF2R 3'UTR is located within the hsa-miR-657 and hsa-miR-453 binding sites. And luciferase reporter assay revealed that hsa-miR-657 acts directly at the 3'UTR of the IGF2R. Furthermore, ACAA-deletion exerted a further repression compared with ACAA-insertion, indicating that hsa-miR-657 regulates IGF2R gene expression in a polymorphic control manner. Importantly, we also demonstrated that hsa-miR-657 can translationally regulate the IGF2R expression levels in Hep G2 cells. Thus, our findings testify the possibility that the ACAA-insertion/deletion polymorphism may result in the change of IGF2R expression levels at least in part by hsa-miR-657-mediated regulation, contributing to the elucidation for the pathogenesis of type 2 diabetes and raise the possibility that miRNAs or in combination with functional DNA sequence polymorphism may be valuable in the treatment of human type 2 diabetes.
Lv
Ke
K
Department of Medical Genetics, Second Military Medical University, 800 XiangYin Road, Shanghai 200433, PR China.
Guo
Yingjun
Y
Zhang
Yiliang
Y
Wang
Kaiyu
K
Jia
Yin
Y
Sun
Shuhan
S
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D019295:Computational Biology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D017384:Sequence Deletion
D020413:3' Untranslated Regions; D035683:MicroRNAs; D017527:Receptor, IGF Type 2