New insights into diabetes onset in response to environmental factors through global transcriptome analysis of pancreatic islets isolated from a mouse model of type 2 diabetes

• Project/Area Number: 26461352
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: NAMMO Takao 国立研究開発法人国立国際医療研究センター, 代謝疾患研究部, 室長 (50594115)
• Co-Investigator(Renkei-kenkyūsha): YASUDA Kazuki 国立国際医療研究センター研究所, 代謝疾患研究部, 部長 (80311611)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: エネルギー・糖代謝異常 / 2型糖尿病 / 膵島 / 環境因子 / エピゲノム / 代償メカニズム / インスリン分泌 / 動物実験 / エネルギー・糖質代謝異常

Outline of Final Research Achievements

Although accumulating evidence supports a role for environmental factors in the development of diabetes, much remains unknown about the molecular mechanisms that are involved in the pathogenesis. Here, we report an analysis of transcriptome of mouse pancreatic islets isolated from a spontaneous mouse model of type 2 diabetes (T2D) exposed to a diabetogenic environment. We also generated genome-wide H3K27ac profiles to detect changes in cis-regulatory activity underlying differential gene expression. Compared to the control condition, we found that the environmental exposure resulted in lots of sites with decreased H3K27ac signals, which were associated to lower expression of corresponding genes. Interestingly, within such regions, there was enrichment of binding motifs for crucial transcription factors, suggesting that epigenetic dysregulation driven by environmental factors can cause downregulation of islet gene expression, beta-cell dysfunction, and the onset and progression of T2D.

Research Products

• [Journal Article] Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. (2017)
  • Author(s): Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, Nozaki Y, Takahashi Y, Ito N, Shibuya A, Ojima H, Sukeda A, Seki Y, Kasama K, Yasuda K, Kanai Y.
  • Journal Title: Carcinogenesis. Volume: 38 Issue: 3 Pages: 261-270
  • DOI: 10.1093/carcin/bgx005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis (2015)
  • Author(s): Saito K, Uebanso T, Maekawa K, Ishikawa M, Taguchi R, Nammo T, Nishimaki-Mogami T, Udagawa H, Fujii M, Shibazaki Y, Yoneyama H, Yasuda K, Saito Y.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 12466-12466
  • DOI: 10.1038/srep12466
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparative analysis of type 2 diabetes-associated SNP alleles identifies allele-specific DNA-binding proteins for the KCNQ1 locus. (2015)
  • Author(s): Hiramoto M, Udagawa H, Watanabe A, Miyazawa K, Ishibashi N, Kawaguchi M, Uebanso T, Nishimura W, Nammo T, Yasuda K.
  • Journal Title: Int J Mol Med. Volume: 36 Issue: 1 Pages: 222-2230
  • DOI: 10.3892/ijmm.2015.2203
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. (2014)
  • Author(s): Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M, Furuta K, Shimada Y, Ogiwara H, Watanabe S, Nokihara H, Yasuda K, Hiramoto M, Nammo T, Ishigame T, Schetter AJ, Okayama H, Harris CC, Kim YH, Mishima M, Yokota J, Yoshida T, Kohno T
  • Journal Title: Clin Cancer Res Volume: 20 Issue: 12 Pages: 3087-3093
  • DOI: 10.1158/1078-0432.ccr-14-0107
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis. (2014)
  • Author(s): Gotoh M, Ichikawa H, Arai E, Chiku S, Sakamoto H, Fujimoto H, Hiramoto M, Nammo T, Yasuda K, Yoshida T, Kanai Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 53 Issue: 12 Pages: 1018-1032
  • DOI: 10.1002/gcc.22211
  • Peer Reviewed / Open Access
• [Presentation] ゲノム網羅的解析結果を用いた膵島代償機序の検討 (2016)
  • Author(s): 南茂隆生、宇田川陽秀、舟橋伸昭、川口美穂、上番増喬、平本正樹、西村渉、安田和基
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] 遺伝子cis調節領域の網羅的解析による膵島代償機序の検討 (2016)
  • Author(s): 南茂隆生、宇田川陽秀、舟橋伸昭、川口美穂、上番増喬、平本正樹、西村渉、安田和基
  • Organizer: 第53回日本臨床分子医学会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-15
• [Presentation] 網羅的cis調節領域の検討による、高脂肪食に続発する膵島代償機序の解明 (2015)
  • Author(s): 南茂 隆生、宇田川 陽秀、舟橋 伸昭、安田 和基
  • Organizer: NGS現場の会 第四回研究会
  • Place of Presentation: 茨城
  • Year and Date: 2015-07-02
• [Presentation] 膵島のゲノム網羅的解析による膵島代償機序/糖尿病発症機序関連因子の同定 (2015)
  • Author(s): 南茂 隆生、宇田川 陽秀、川口 美穂、舟橋 伸昭、上番増 喬、平本 正樹、西村 渉、安田 和基
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 山口
  • Year and Date: 2015-05-21
• [Presentation] 膵島のゲノム網羅的解析による糖尿病発症機序の考察 (2014)
  • Author(s): 南茂隆生、宇田川陽秀、川口美穂、舟橋伸昭、上番増喬、平本正樹、西村渉、安田和基
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-24
• [Book] 膵β細胞分化過程におけるエピゲノム変化、内分泌・糖尿病・代謝内科 (2014)
  • Author(s): 南茂 隆生、安田 和基
  • Total Pages: 8
  • Publisher: 科学評論社
• [Remarks] 代謝疾患研究部
  • URL: http://www.rincgm.jp/department/dia/02/