Analysis of the mechanism of diabetes onset by long non-coding RNA; lincRNA-p21.

• Project/Area Number: 21K20666
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0702:Biology at cellular to organismal levels, and related fields
• Research Institution: Hyogo Medical University
• Principal Investigator: IMASAKA Mai 兵庫医科大学, 医学部, 助教 (50759553)
• Project Period (FY): 2021-08-30 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: lincRNA / シス機能 / エンハンサー / incRNA-p21 / p21 / 糖尿病 / β細胞 / lincRNA-p21 / 長鎖非コードRNA

Outline of Research at the Start

長鎖非コードRNA；lincRNA-p21を、内在性遺伝子座（本来の遺伝子の位置）で過剰発現させたマウスは糖尿病を自然発症することを見いだした。これまでの解析から発症の鍵は上流p21遺伝子の転写亢進と予測される。本研究では、lincRNA-p21によるp21の転写調節機構、lincRNA-p21やp21の糖尿病との関わりについて解明する。lincRNA-p21はヒトのがん細胞で発現の変動が見られることからバイオマーカーや治療ターゲットとしても期待されている分子であり、機能および機序の解明はその実用化に向けても重要な知見となる。

Outline of Final Research Achievements

Mice overexpressing lincRNA-p21 at the endogenous locus spontaneously develop diabetes with reduced insulin secretion. Previous analyses have shown that transcriptional activation of the upstream p21 gene is the cause of diabetes onset. To investigate the mechanism of p21 transcriptional enhancement by lincRNA-p21, we generated mice overexpressing EGFP at the endogenous locus and EGFP-overexpressing; lincRNA-p21 exon 1-deleted mice. We examined whether these two strains had high p21 expression and developed diabetes. As a result, high p21 expression and diabetes onset were confirmed in both mice, suggesting that lincRNA-p21 enhances p21 transcription not as an RNA but as an enhancer.

Academic Significance and Societal Importance of the Research Achievements

lincRNA-p21は、細胞周期、アポトーシス、細胞増殖、腫瘍形成、浸潤、転移、血管新生といった多様な機能が報告されている（Int. J. Mol. Sci., 2015）。また、ヒトのがん細胞で発現の変動が見られることからバイオマーカーとしても期待されており（Cell Biosci, 2020）、機能および作用機序の解明はその実用化に向けても重要な知見となる。また、本マウスは肥満や小胞体ストレスを伴わない新たなインスリン分泌低下型の糖尿病モデルマウスである。膵β細胞数の減少は全ての糖尿病患者で見られる病態であり、p21を介した新たな膵β細胞減少機構の解明は、糖尿病の原因や治療につながる。

Research Products

• [Journal Article] Reg family proteins contribute to inflammation and pancreatic stellate cells activation in chronic pancreatitis (2023)
  • Author(s): Chen Wenting、Imasaka Mai、Lee Miyu、Fukui Hirokazu、Nishiura Hiroshi、Ohmuraya Masaki
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 12201-12201
  • DOI: 10.1038/s41598-023-39178-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tmem161a regulates bone formation and bone strength through the P38 MAPK pathway (2023)
  • Author(s): Nagai Takuya、Sekimoto Tomohisa、Kurogi Syuji、Ohta Tomomi、Miyazaki Shihoko、Yamaguchi Yoichiro、Tajima Takuya、Chosa Etsuo、Imasaka Mai、Yoshinobu Kumiko、Araki Kimi、Araki Masatake、Choijookhuu Narantsog、Sato Katsuaki、Hishikawa Yoshitaka、Funamoto Taro
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 14639-14639
  • DOI: 10.1038/s41598-023-41837-4
  • Peer Reviewed / Open Access
• [Journal Article] Beclin1 is essential for the pancreas development (2023)
  • Author(s): Mehanna Sally、Arakawa Satoko、Imasaka Mai、Chen Wenting、Nakanishi Yuto、Nishiura Hiroshi、Shimizu Shigeomi、Ohmuraya Masaki
  • Journal Title: Developmental Biology Volume: 504 Pages: 113-119
  • DOI: 10.1016/j.ydbio.2023.09.008
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis (2023)
  • Author(s): Tsuchiya Y, Seki T, Kobayashi K, Komazawa-Sakon S, Shichino S, Nishina T, Fukuhara K, Ikejima K, Nagai H, Igarashi Y, Ueha S, Oikawa A, Tsurusaki S, Yamazaki S, Nishiyama C, Mikami T, Yagita H, Okumura K, Kido T, Miyajima A, Matsushima K, Imasaka M, Araki K, Imamura T, Ohmuraya M, Tanaka M, Nakano H
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 6304-6304
  • DOI: 10.1038/s41467-023-42058-z
  • Peer Reviewed / Open Access
• [Presentation] lincRNA-p21遺伝子座による上流p21遺伝子の転写調節機構の解明 (2023)
  • Author(s): 今坂 舞、奥野 美佐子、荒木 正健、荒木 喜美、大村谷 昌樹
  • Organizer: 日本遺伝学会 第95回大会
• [Presentation] Mice overexpressing the Trp53cor1 (lincRNA-p21) gene at the endogenous locus develop diabetes. (2023)
  • Author(s): Mai Imasaka, Masatake Araki, Kimi Araki, Masaki Ohmuraya.
  • Organizer: International Mammalian Genome Conference
  • Int'l Joint Research