論文 - 詳細
| RRC ID | 69290 |
|---|---|
| 著者 | Zhou B, Wei FY, Kanai N, Fujimura A, Kaitsuka T, Tomizawa K. |
| タイトル | Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human. |
| ジャーナル | Hum Mol Genet |
| Abstract |
Single-nucleotide polymorphisms (SNPs) in CDKAL1 have been associated with the development of type 2 diabetes (T2D). CDKAL1 catalyzes 2-methylthio modification of adenosine at position 37 of tRNA(Lys)(UUU). A deficit of this modification causes aberrant protein synthesis, and is associated with impairment of insulin secretion in both mouse model and human. However, it is unknown whether the T2D-associated SNPs in CDKAL1 are associated with downregulation of CDKAL1 by regulating the gene expression. Here, we report a specific splicing variant of CDKAL1 termed CDKAL1-v1 that is markedly lower in individuals carrying risk SNPs of CDKAL1. Interestingly, CDKAL1-v1 is a non-coding transcript, which regulates the CDKAL1 level by competitive binding to a CDKAL1-targeting miRNA. By direct editing of the genome, we further show that the nucleotides around the SNP regions are critical for the alternative splicing of CDKAL1-v1. These findings reveal that the T2D-associated SNPs in CDKAL1 reduce CDKAL1-v1 levels by impairing splicing, which in turn increases miRNA-mediated suppression of CDKAL1. Our results suggest that CDKAL1-v1-mediated suppression of CDKAL1 might underlie the pathogenesis of T2D in individuals carrying the risk SNPs. |
| 巻・号 | 23(17) |
| ページ | 4639-50 |
| 公開日 | 2014-9-1 |
| DOI | 10.1093/hmg/ddu184 |
| PII | ddu184 |
| PMID | 24760768 |
| MeSH | Alleles Alternative Splicing / genetics* Animals Base Sequence Cyclin-Dependent Kinase 5 / genetics* Cyclin-Dependent Kinase 5 / metabolism Diabetes Mellitus, Type 2 / genetics* Genetic Predisposition to Disease* HEK293 Cells HeLa Cells Humans Insulin / metabolism Insulin Secretion Mice MicroRNAs / metabolism Molecular Sequence Data Open Reading Frames / genetics* Polymorphism, Single Nucleotide / genetics RNA, Messenger / genetics RNA, Messenger / metabolism RNA, Untranslated / genetics RNA, Untranslated / metabolism Risk Factors tRNA Methyltransferases |
| IF | 5.101 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 293(RCB1637) |