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

Xianying Piao; Naoya Yahagi; Yoshinori Takeuchi; Yuichi Aita; Yuki Murayama; Yoshikazu Sawada; Akito Shikama; Yukari Masuda; Makiko Nishi-Tatsumi; Midori Kubota; Yoshihiko Izumida; Motohiro Sekiya; Takashi Matsuzaka; Yoshimi Nakagawa; Yoko Sugano; Hitoshi Iwasaki; Kazuto Kobayashi; Shigeru Yatoh; Hiroaki Suzuki; Hiroaki Yagyu; Yasushi Kawakami; Hitoshi Shimano

doi:10.1002/1873-3468.12975

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

Xianying Piao, Naoya Yahagi^*, Yoshinori Takeuchi, Yuichi Aita, Yuki Murayama, Yoshikazu Sawada, Akito Shikama, Yukari Masuda, Makiko Nishi-Tatsumi, Midori Kubota, Yoshihiko Izumida, Motohiro Sekiya, Takashi Matsuzaka, Yoshimi Nakagawa, Yoko Sugano, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Hiroaki Suzuki, Hiroaki YagyuYasushi Kawakami, Hitoshi Shimano

^*この論文の責任著者

和漢医薬学総合研究所研究開発部門複雑系解析分野

研究成果: ジャーナルへの寄稿 › 学術論文 › 査読

7 被引用数 (Scopus)

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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.

本文言語	英語
ページ（範囲）	422-433
ページ数	12
ジャーナル	FEBS Letters
巻	592
号	3
DOI	https://doi.org/10.1002/1873-3468.12975
出版ステータス	出版済み - 2018/02

ASJC Scopus 主題領域

生物理学
構造生物学
生化学
分子生物学
遺伝学
細胞生物学

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

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10.1002/1873-3468.12975

引用スタイル

Piao, X., Yahagi, N., Takeuchi, Y., Aita, Y., Murayama, Y., Sawada, Y., Shikama, A., Masuda, Y., Nishi-Tatsumi, M., Kubota, M., Izumida, Y., Sekiya, M., Matsuzaka, T., Nakagawa, Y., Sugano, Y., Iwasaki, H., Kobayashi, K., Yatoh, S., Suzuki, H., ... Shimano, H. (2018). A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes. FEBS Letters, 592(3), 422-433. https://doi.org/10.1002/1873-3468.12975

@article{0f8a95468766461e8f8a75aed184488b,

title = "A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes",

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",

author = "Xianying Piao and Naoya Yahagi and Yoshinori Takeuchi and Yuichi Aita and Yuki Murayama and Yoshikazu Sawada and Akito Shikama and Yukari Masuda and Makiko Nishi-Tatsumi and Midori Kubota and Yoshihiko Izumida and Motohiro Sekiya and Takashi Matsuzaka and Yoshimi Nakagawa and Yoko Sugano and Hitoshi Iwasaki and Kazuto Kobayashi and Shigeru Yatoh and Hiroaki Suzuki and Hiroaki Yagyu and Yasushi Kawakami and Hitoshi Shimano",

note = "Publisher Copyright: {\textcopyright} 2018 Federation of European Biochemical Societies",

year = "2018",

month = feb,

doi = "10.1002/1873-3468.12975",

language = "英語",

volume = "592",

pages = "422--433",

journal = "FEBS Letters",

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Piao, X, Yahagi, N, Takeuchi, Y, Aita, Y, Murayama, Y, Sawada, Y, Shikama, A, Masuda, Y, Nishi-Tatsumi, M, Kubota, M, Izumida, Y, Sekiya, M, Matsuzaka, T, Nakagawa, Y, Sugano, Y, Iwasaki, H, Kobayashi, K, Yatoh, S, Suzuki, H, Yagyu, H, Kawakami, Y & Shimano, H 2018, 'A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes', FEBS Letters, vol. 592, no. 3, pp. 422-433. https://doi.org/10.1002/1873-3468.12975

TY - JOUR

T1 - A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes

AU - Piao, Xianying

AU - Yahagi, Naoya

AU - Takeuchi, Yoshinori

AU - Aita, Yuichi

AU - Murayama, Yuki

AU - Sawada, Yoshikazu

AU - Shikama, Akito

AU - Masuda, Yukari

AU - Nishi-Tatsumi, Makiko

AU - Kubota, Midori

AU - Izumida, Yoshihiko

AU - Sekiya, Motohiro

AU - Matsuzaka, Takashi

AU - Nakagawa, Yoshimi

AU - Sugano, Yoko

AU - Iwasaki, Hitoshi

AU - Kobayashi, Kazuto

AU - Yatoh, Shigeru

AU - Suzuki, Hiroaki

AU - Yagyu, Hiroaki

AU - Kawakami, Yasushi

AU - Shimano, Hitoshi

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

KW - enhancer

KW - functional SNP

KW - transcription factor

KW - type 2 diabetes

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U2 - 10.1002/1873-3468.12975

DO - 10.1002/1873-3468.12975

M3 - 学術論文

C2 - 29331016

AN - SCOPUS:85040778196

SN - 0014-5793

VL - 592

SP - 422

EP - 433

JO - FEBS Letters

JF - FEBS Letters

IS - 3

ER -

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

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ASJC Scopus 主題領域

UN SDG

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