| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| 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.
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