Molecular mechanism of Cdkal1 single nucleotide polymorphism-dependent type 2 diabetes

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860753
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: WEI Fan-Yan 熊本大学, 生命科学研究部, 助教 (90555773)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 糖尿病 / tRNA / 修飾

Outline of Final Research Achievements

SNPs in CDKAL1 is one of the most reliable risk factors for type 2 diabetes (T2D). However, the molecular mechanism by which the intronic single nucleotide polymorphisms (SNPs) contribute to T2D has been unclear. This study revealed the SNPs as actively involved in the regulation of cellular CDKAL1 levels through a unique post-transcriptional mechanism. A specific splicing variant of CDKAL1 (CDKAL1-v1) was drastically decreased in individuals carrying the risk SNPs in CDKAL1. CDKAL1-v1 is a non-coding transcript, which regulates Cdkal1 level by the competitive binding of a CDKAL1-targeting microRNA. By direct editing of genome in human cell lines, this study further shows that the nucleotides around the SNPs regions are critical for the alternative splicing of CDKAL1-v1. These findings demonstrate that the T2D-associated SNPs in CDKAL1 directly contribute to the decrease in CDKAL1-v1 by impairing splicing, which in turn induces microRNA-mediated suppression of cellular CDKAL1 level.

Free Research Field

生理学