Molecular basis for Jmjd6-mediated control of Aire protein expression and its evolutional insight
| Project/Area Number |
16H02497
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Kyushu University |
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Principal Investigator |
Fukui Yoshinori 九州大学, 生体防御医学研究所, 教授 (60243961)
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| Co-Investigator(Kenkyū-buntansha) |
宇留野 武人 九州大学, 生体防御医学研究所, 准教授 (80532093)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000)
Fiscal Year 2018: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
Fiscal Year 2017: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2016: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
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| Keywords | 発現制御 / 遺伝子 / 生体分子 |
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| Outline of Final Research Achievements |
Jmjd6 is a member of the JmjC-domain containing proteins that are involved in a wide range of oxidation reactions. Jmjd6 catalyses lysyl hydroxylation of multiple substrates, including splicing regulatory proteins, transcription factors and histones, in a manner dependent on the Fe(II) and 2-oxoglutarate. We found that Jmjd6 plays a key role in induction of central tolerance by controlling Aire expression in mTECs. Although Jmjd6 deficiency did not affect abundance of Aire transcript, the intron 2 of Aire gene was not effectively spliced out in the absence of Jmjd6, owing to the unique 3’ splice site sequence. As a result, the expression of Aire protein was markedly reduced in Jmjd6-deficient mTECs, and T cells generated in such thymic microenvironments caused multi-organ autoimmunity in mice. In this project, we have analyzed the mechanism for Jmjd6-mediated control of Aire RNA splicing and revealed several functions of Jmjd6.
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| Academic Significance and Societal Importance of the Research Achievements |
intron retentionはミススプライシングの結果であるとの考えから、その生物学的重要性は見過ごされて来た。しかしながら研究代表者は、Aireのタンパク質発現が、intron retentionにより、２段階の制御を受けることを発見した。Aireはpromiscuousな遺伝子発現を誘導する「危ない遺伝子」であり、その発現は厳密にコントロールされている必要があると推測されてきたが、それがこのような２段階制御機構によって担われていることは、全く予想外であった。本研究の成果は、タンパク質の機能発現制御における新たなパラダイムの創出につながることが期待される。
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Report
(4 results)
Research Products
(26 results)
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[Journal Article] Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye.2018
Author(s)
Sakurai T, Uruno T, Sugiura Y, Tatsuguchi T, Yamamura K, Ushijima M, Hattori Y, Kukimoto-Niino M, Mishima-Tumagari C, Watanabe M, Suematsu M, Fukui Y
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Journal Title
Science Signaling
Volume: 11
Issue: 541
Pages: 1-11
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activation Rac1P29S mutation.2018
Author(s)
Tomino T, Tajiri H, Tatsuguchi T, Shirai T, Oisaki K, Matsunaga S, Sanematsu F, Sakata D, Yoshizumi T, Maehara Y, Kanai M, Cote JF, Fukui Y, Uruno T
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Journal Title
Biochem.Biophys.Res.Commun.
Volume: 497
Issue: 1
Pages: 298-304
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A functional genomics predictive network model identifies regulators of inflammatory bowel disease.2017
Author(s)
Peters LA, Perrigoue J, Mortha A, Iuga A, Song WM, Neiman EM, Llewellyn SR, Di Narzo A, Kidd BA, Telesco SE, Zhao Y, Stojmirovic A, Sendecki J, Shameer K, Miotto R, Losic B, Shah H, Lee E, Wang M, Faith JJ, Kasarskis A, Brodmerkel C, Curran M, Das A, Friedman JR, Fukui Y, et al
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Journal Title
Nature Genet.
Volume: 49
Issue: 10
Pages: 1437-1449
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Targeting Ras-driven cancer cell survival and invasion through selective inhibition of DOCK12017
Author(s)
Tajiri H, Uruno T, Shirai T, Takaya D, Matsunaga S, Setoyama D, Watanabe M, Kukimoto-Niino M, Oisaki K, Ushijima M, Sanematsu F, Honma T, Terada T, Oki E, Shirasawa S, Maehara Y, Kang D, Cote J-F, Yokoyama S, Kanai M, Fukui Y
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Journal Title
Cell Reports
Volume: 19
Issue: 5
Pages: 969-980
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction.2017
Author(s)
Yamamura K, Uruno T, Shiraishi A, Tanaka Y, Ushijima M, Nakahara T, Watanabe M, Kido-Nakahara M, Tsuge I, Furue M, Fukui Y.
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Journal Title
Nat Commun
Volume: 8
Issue: 1
Pages: 13946-13946
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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