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.

[1]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[2]  T. V. van Haeften,et al.  Insulin‐like growth factors and pancreas beta cells , 2004, European journal of clinical investigation.

[3]  Chaoqian Xu,et al.  The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 , 2011, Nature Medicine.

[4]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[5]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Iwata,et al.  Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Banerjee,et al.  A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance , 2007, Proceedings of the National Academy of Sciences.

[8]  P. O'Connell,et al.  A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. , 2001, American journal of human genetics.

[9]  Thomas D. Schmittgen,et al.  The Human Angiotensin II Type 1 Receptor +1166 A/C Polymorphism Attenuates MicroRNA-155 Binding* , 2007, Journal of Biological Chemistry.

[10]  R. Aitken,et al.  Identification of the Insulin-Like Growth Factor II Receptor as a Novel Receptor for Binding and Invasion by Listeria monocytogenes , 2006, Infection and Immunity.

[11]  G. Gill,et al.  The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor , 2003, Oncogene.

[12]  R. Baxter,et al.  Regulation of soluble insulin-like growth factor II/mannose 6-phosphate receptor in human serum: measurement by enzyme-linked immunosorbent assay. , 1999, The Journal of clinical endocrinology and metabolism.

[13]  Vesselin Baev,et al.  MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence , 2005, Nucleic Acids Res..

[14]  C. Croce,et al.  MicroRNA-133 controls cardiac hypertrophy , 2007, Nature Medicine.

[15]  J. J. Robinson,et al.  Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture , 2001, Nature Genetics.

[16]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[17]  Murat Gunel,et al.  Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome , 2005, Science.

[18]  Michel Georges,et al.  Polymorphic miRNA-mediated gene regulation: contribution to phenotypic variation and disease. , 2007, Current opinion in genetics & development.

[19]  C. Gicquel,et al.  Epigenetic abnormalities of the mannose-6-phosphate/IGF2 receptor gene are uncommon in human overgrowth syndromes , 2004, Journal of Medical Genetics.

[20]  W. Rutter,et al.  Insulin-like growth factor II receptor as a multifunctional binding protein , 1987, Nature.

[21]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[22]  J. Fernández-Real,et al.  The ACAA-insertion/deletion polymorphism at the 3' UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance. , 2006, European journal of endocrinology.

[23]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[24]  R. Barale,et al.  A catalog of polymorphisms falling in microRNA-binding regions of cancer genes. , 2008, DNA and cell biology.

[25]  Florian Caiment,et al.  A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep , 2006, Nature Genetics.