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FEBS Lett. 2018 Feb;592(3):422-433. doi: 10.1002/1873-3468.12975. Epub 2018 Jan 23.

A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes.

Author information

1
Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
2
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Abstract

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.

KEYWORDS:

enhancer; functional SNP; transcription factor; type 2 diabetes

PMID:
29331016
DOI:
10.1002/1873-3468.12975
[Indexed for MEDLINE]
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