イントロン構造を介した遺伝子発現特異性の制御

• Project Area: Functions of non-coding DNA region for genome integrity
• Project/Area Number: 26114720
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 谷内 一郎 国立研究開発法人理化学研究所, 統合生命医科学研究センター, グループディレクター (20284573)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: イントロン構造 / ゲノム機能 / 遺伝子発現制御

Outline of Annual Research Achievements

ゲノムの中でタンパクをコードしない非コード領域が関与する遺伝子発現制御機構としてエンハンサー等の古典的なシス制御領域を介した制御機構に関しては多くの知見が蓄積されて来た。一方でトランスジェニック動物作製の際には外来性遺伝子の高発現には、古典的なシス制御領域に加えRNAスプライシングを可能とするイントロン構造の付加が必要であることが知られており、この現象は"intron-mediated enhancement"と呼ばれてきた。
胸腺内でのT細胞分化過程ではCd8遺伝子の分化段階且つ系列特異的な再活性化による動的な発現パターンが重要であるが、その制御機構の実体は良く解っていない。研究代表者はhCD2遺伝子cDNAをマウスCd8a遺伝子座にノックイン挿入することで作製した種々のCD8-hCD2レポーターアレルの発現解析より、Cd8遺伝子の再活性化にはイントロン構造が必要であること発見した。この観察結果はイントロン構造を介した制御が単なる遺伝子発現量の制御のみならず、発現特異性の制御にも関与することを示していることから、本研究課題ではその分子実体を明らかにすることを目的と研究を行った。
その結果、RNAスプライシングに必要なスプライシングドナー/アクセプター配列ヘの特異的な変異挿入ではCD8-hCD2レポーターアレルの発現は対照群に比較して顕著な影響をうけなかったことから、予想に反してRNAスプライシングそのものは必須でないこと、イントロン構造はエンハンサーを介したDNA脱メチル化に関与すること、内在性Cd8a遺伝子の発現におけるイントロン構造を介した制御機構はCD8-hCD2レポーターアレルと異なる可能性がある結果を得た。本研究間内では分子実体は完全に解明出来なかったが、今後は長鎖非コードRNAの関与に着目して研究を継続したい。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Views on helper/cytotoxic lineage choice from a bottom-up approach. (2016)
  • Author(s): Taniuchi I
  • Journal Title: Immunol Rev. Volume: 271 Issue: 1 Pages: 98-113
  • DOI: 10.1111/imr.12401
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1: implications in repression of CD40L expression in CD8+ cytotoxic T cells. (2016)
  • Author(s): Tsuchiya Y, Naito T, Tenno M, Maruyama M, Koseki H, Taniuchi I, Naoe Y.
  • Journal Title: J Leukoc Biol. Volume: 印刷中 Issue: 2 Pages: 327-338
  • DOI: 10.1189/jlb.1a0915-396rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MAZR and Runx factors synergistically repress ThPOK during CD8+ T cell lineage development. (2015)
  • Author(s): Sakaguchi S, Hainberger D, Tizian C, Tanaka H, Okuda T, Taniuchi I, Ellmeier W
  • Journal Title: Journal of Immunology Volume: 195 Issue: 6 Pages: 2879-2887
  • DOI: 10.4049/jimmunol.1500387
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development (2015)
  • Author(s): Bingtao Hao, Abani Kanta Naik , Akiko Watanabe , Hirokazu Tanaka , Liang Chen , Hunter W Richards, Motonari Kondo, Ichiro Taniuchi, Yoshinori Kohwi, Terumi Kohwi-Shigematsu, Michael S Krangel
  • Journal Title: Journal of experimental medicine Volume: 212 Issue: 5 Pages: 809-824
  • DOI: 10.1084/jem.20142207
  • Peer Reviewed
• [Journal Article] A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells. (2015)
  • Author(s): Sakaguchi S, Hombauer M, Hassan H, Tanaka H, Yasmin N, Naoe Y, Bilic I, Moser MA, Hainberger D, Mayer H, Seiser C, Bergthaler A, Taniuchi I, Ellmeier W.
  • Journal Title: J Leukoc Biol. Volume: 97 Issue: 4 Pages: 635-644
  • DOI: 10.1189/jlb.1hi1113-597rr
  • Peer Reviewed
• [Journal Article] Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element. (2015)
  • Author(s): Majumder K, Koues O, Chan E, Kyle K, Horowitz J, Yang-Iott K, Bassing C, Taniuchi I, Krangel M, Oltz E
  • Journal Title: J.Exp.Med. Volume: 212 Issue: 1 Pages: 107-20
  • DOI: 10.1084/jem.20141479
  • Peer Reviewed
• [Journal Article] Runx/Cbfb signaling regulates postnatal development of granular convoluted tubule in the mouse submandibular gland. (2015)
  • Author(s): Islam MN, Itoh S, Yanagita T, Sumiyoshi K, Hayano S, Kuremoto K, Kurosaka H, Honjo T, Kawanabe N, Kamioka H, Sakai T, Ishimaru N, Taniuchi I, Yamashiro T
  • Journal Title: Dev Dyn. Volume: 244(3) Issue: 3 Pages: 488-496
  • DOI: 10.1002/dvdy.24231
  • Peer Reviewed / Open Access
• [Journal Article] Cbfb regulates bone development by stabilizing Runx family proteins. (2015)
  • Author(s): Qin X, Jiang Q, Matsuo Y, Kawane T, Komori H, Moriishi T, Taniuchi I, Ito K, Kawai Y, Rokutanda S, Izumi S, Komori T.
  • Journal Title: Journal of bone and mineral research Volume: 30 Issue: 4 Pages: 706-714
  • DOI: 10.1002/jbmr.2379
  • Peer Reviewed
• [Journal Article] Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development. (2014)
  • Author(s): Mishima Y, Wang C, Miyagi S, Saraya A, Hosokawa H, Mochizuki-Kashio M, Nakajima-Takagi Y, Koide S, Negishi M, Sashida G, Naito T, Ishikura T, Onodera A, Nakayama T, Tenen DG, Yamaguchi N, Koseki H, Taniuchi I, Iwama A.
  • Journal Title: Nature Communications Volume: 18 Issue: 1 Pages: 5872-5882
  • DOI: 10.1038/ncomms6872
  • Peer Reviewed / Open Access
• [Journal Article] Cbfb deficiency results in differentiation blocks and stem/progenitor cell expansion in hematopoiesis. (2014)
  • Author(s): Wang CQ, Chin DW, Chooi JY, Wee Joo C, Taniuchi I, Tergaonkar V, Osato M.
  • Journal Title: Leukemia Volume: 29 Issue: 3 Pages: 753-7
  • DOI: 10.1038/leu.2014.316
  • Peer Reviewed / Open Access
• [Journal Article] The Role of BTB-Zinc Finger Transcription Factors During T Cell Development and in the Regulation of T Cell-mediated Immunity. (2014)
  • Author(s): Ellmeier W, Taniuchi I.
  • Journal Title: Curr Top Microbiol Immunol. Volume: 381 Pages: 21-49
  • DOI: 10.1007/82_2014_374
  • ISBN: 9783319073941, 9783319073958
• [Journal Article] Functional B-1 progenitor cells are present in the hematopoietic stem cell deficient embryo and depend on Cbfβ for their development. (2014)
  • Author(s): Kobayashi M, Shelly CW, Seo W, Vemula S, Liu Y, Taniuchi I and Yoshimoto M.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 111 Issue: 33 Pages: 12151-6
  • DOI: 10.1073/pnas.1407370111
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. (2014)
  • Author(s): Wang CQ, Krishnan V, Tay LS, Chin DW, Koh CP, Chooi JY, Nah GS, Du L, Jacob B, Yamashita N, Lai SK, Tan TZ, Mori S, Taniuchi I, Tergaonkar V, Ito Y, Osato M.
  • Journal Title: Cell Reports Volume: 8 Pages: 767-82
  • Peer Reviewed / Open Access
• [Journal Article] CD4^+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2 (2014)
  • Author(s): Boucheron N, Tschismarov R, Goeschl L, Moser M.A, Lagger S, Sakaguchi S, Winter M, Lenz F, Vitko D, Breitwieser FP, Muller L, Hassan H, Bennett K.L, Colinge J, Schreiner W, Egawa T, Taniuchi I, Matthias P, Seiser C Ellmeier W
  • Journal Title: Nat. Immunol Volume: 15 Issue: 5 Pages: 439-448
  • DOI: 10.1038/ni.2864
  • Peer Reviewed / Open Access
• [Presentation] Repression of CCL5 by Runx/Cbfb is essential to prevent lung infiltration (2015)
  • Author(s): Taniuchi I
  • Organizer: Runx2015
  • Place of Presentation: Rehovot, Israel
  • Year and Date: 2015-10-20
  • Int'l Joint Research / Invited
• [Presentation] Linking environment cues with mechanisms that control specification of T lymphocyte lineages requires a proper positioning of regulatory regions (2015)
  • Author(s): Taniuchi I
  • Organizer: EMBO conference
  • Place of Presentation: Paris, France
  • Year and Date: 2015-10-01
  • Int'l Joint Research
• [Presentation] Roles of SATB1 during Thymocyte Development (2015)
  • Author(s): Taniuchi I
  • Organizer: FASEB Conference
  • Place of Presentation: Montana, USA.
  • Year and Date: 2015-08-18
  • Int'l Joint Research
• [Presentation] Transcriptional Regulation of T Cell Development in the Thymus (2015)
  • Author(s): Taniuchi I
  • Organizer: Keystone Symposium
  • Place of Presentation: Snowbirds, USA
  • Year and Date: 2015-04-01
  • Int'l Joint Research / Invited
• [Presentation] Cell fate determination in the thymus (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 43rd Annual Meeting of Japanese Society of Immunology
  • Place of Presentation: 京都
  • Year and Date: 2014-12-11
  • Invited
• [Presentation] Road to become CD4 helper T cells (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: Seminar at Duke University Medical Center, Department of Immunology
  • Place of Presentation: Durham, NC, USA
  • Year and Date: 2014-11-13
  • Invited
• [Presentation] Road to become CD4 helper T Cells (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: Seminar at Washington University in St. Louis, School of Medicine, Department of Pathology & Immunology
  • Place of Presentation: Saint Louis, MO, USA
  • Year and Date: 2014-11-11
  • Invited
• [Presentation] Transcriptional regulation of CD4/CD8 lineage choice: roles of Bcl11b and SATB1 (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: France - Japan Immunology meeting
  • Place of Presentation: Cassis, France
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] Roles of Runx Transcription Factor Family During T Lymphocyte Development (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: SIgN Immunology Seminar
  • Place of Presentation: Singapore
  • Year and Date: 2014-08-28
  • Invited
• [Presentation] Transcriptional Control of Helper/Cytotoxic Lineage Choice in The Thymus (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: RIKEN IMS-JSI International Symposium on Immunology 2014
  • Place of Presentation: 横浜
  • Year and Date: 2014-06-26
  • Invited
• [Presentation] Regulation of CD4 helper versus Cd8 cytotoxic lineage choice by transcription factors (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: AIM Series Seminar
  • Place of Presentation: Pohang, Korea
  • Year and Date: 2014-05-21
  • Invited
• [Presentation] Regulation of local chromatin loop at the Thpok in the CD4/CD8 lineage decision (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 24th Kyoto T Cell Conference (KTCC 2014)
  • Place of Presentation: 京都
  • Year and Date: 2014-05-16
• [Presentation] Transcriptional conotrol of helper/cytotoxic lineage choice in the thymus (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: AAI Immunology 2014
  • Place of Presentation: Pittsburgh, Pennsylvania, USA
  • Year and Date: 2014-05-05
  • Invited
• [Presentation] Regulation of local chromatin loop at the Thpok in the CD4/CD8 lineage decision by Bcl11b and SATB1 (2014)
  • Author(s): Ichiro Taniuchi
  • Organizer: Gene Expression & Signaling in the Immune System
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2014-04-23