A candidate functional SNP rs7074440 inTCF7L2alters gene expression through C-FOS in hepatocytes
| Autor: | Yoko Sugano, Yuki Murayama, Takashi Matsuzaka, Hiroaki Yagyu, Motohiro Sekiya, Yasushi Kawakami, Yukari Masuda, Xianying Piao, Naoya Yahagi, Yuichi Aita, Hitoshi Iwasaki, Kazuto Kobayashi, Akito Shikama, Yoshinori Takeuchi, Yoshimi Nakagawa, Midori Kubota, Makiko Nishi-Tatsumi, Shigeru Yatoh, Hiroaki Suzuki, Hitoshi Shimano, Yoshihiko Izumida, Yoshikazu Sawada |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine endocrine system endocrine system diseases Biophysics Gene Expression Locus (genetics) Biology Polymorphism Single Nucleotide Biochemistry Cell Line Mice 03 medical and health sciences Structural Biology Gene expression Genetics Animals Humans SNP Allele Enhancer Molecular Biology Transcription factor Gene knockdown nutritional and metabolic diseases Hep G2 Cells Cell Biology Molecular biology HEK293 Cells 030104 developmental biology Diabetes Mellitus Type 2 Hepatocytes Female Proto-Oncogene Proteins c-fos Transcription Factor 7-Like 2 Protein TCF7L2 |
| Zdroj: | FEBS Letters. 592:422-433 |
| ISSN: | 0014-5793 |
| DOI: | 10.1002/1873-3468.12975 |
| Popis: | The SNP rs7903146 at the transcription factor 7-like 2 (TCF7L2) locus is established as the strongest known genetic marker for type 2 diabetes via genome-wide association studies. However, the functional SNPs regulating TCF7L2 expression remain unclear. Here, we show that the SNP rs7074440 is a candidate functional SNP highly linked with rs7903146. A reporter plasmid with rs7074440 normal allele sequence exhibited 15-fold higher luciferase activity compared with risk allele sequence in hepatocytes, demonstrating a strong enhancer activity at rs7074440. Additionally, we identified C-FOS as an activator binding to the rs7074440 enhancer using a TFEL genome-wide screen method. Consistently, knockdown of C-FOS significantly reduced TCF7L2 expression in hepatocytes. Collectively, a novel enhancer regulating TCF7L2 expression was revealed through searching for functional SNPs. |
| Databáze: | OpenAIRE |
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