Epigenetics in osteoclastogenesis

• Project/Area Number: 26253075
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: TANAKA Sakae 東京大学, 医学部附属病院, 教授 (50282661)
• Co-Investigator(Kenkyū-buntansha): 廣瀬 旬 東京大学, 医学部附属病院, 助教 (00456112) ; 武冨 修治 東京大学, 医学部附属病院, 講師 (70570018) ; 門野 夕峰 東京大学, 医学部附属病院, 准教授 (70401065) ; 田中 滋之 東京大学, 医学部附属病院, その他 (10645857) ; 安井 哲郎 東京大学, 医学部附属病院, 講師 (30583108)
• Co-Investigator(Renkei-kenkyūsha): ABURATANI Hiroyuki 東京大学, 先端科学技術研究センター, 教授 (10202657)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥41,340,000 (Direct Cost: ¥31,800,000、Indirect Cost: ¥9,540,000); Fiscal Year 2017: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2016: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2015: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2014: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
• Keywords: 破骨細胞 / エピジェネティクス / 次世代シーケンサー / PU.1 / IRF8 / NFATc1 / 骨代謝学 / シグナル伝達

Outline of Final Research Achievements

RANKL induces osteoclast (OC) differentiation from bone marrow-derived macrophages (BMMs). NFATc1 and IRF8 play positive and negative roles, respectively, in this process. We used chromatin immunoprecipitation and formaldehyde-assisted isolation of regulatory elements followed by sequencing to show that PU.1 transcription factor binding motifs were overrepresented at active cis-regulatory regions in both murine BMMs and OCs, while IRF and NFAT binding motifs were selectively enriched at these regions in BMMs and OCs, respectively.
BMM-specific PU.1 binding sites were observed to overlap with IRF8 binding sites in BMMs, and this also occurred for OC-specific PU.1 binding sites and NFATc1 binding sites in OCs. Our results suggest that PU.1 switches its transcription partner from IRF8 to NFATc1, and alters the binding regions during RANKL-induced osteoclastogenesis, which is associated with changes in epigenetic profiles and the control of cell-type specific gene expression.

Research Products

• [Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1. (2017)
  • Author(s): Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: e0175632-e0175632
  • DOI: 10.1371/journal.pone.0175632
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced osteoclastogenesis (2015)
  • Author(s): Omata Y, Yasui T, Hirose J, Izawa N, Imai Y, Matsumoto T, Masuda H, Tokuyama N, Nakamura S, Tsutsumi S, Yasuda H, Okamoto K, Takayanagi H, Hikita A, Imamura T, Matsuo K, Saito T, Kadono Y, Aburatani H, Tanaka S
  • Journal Title: J Bone Miner Res. Volume: 30 Issue: 5 Pages: 869-77
  • DOI: 10.1002/jbmr.2418
  • Peer Reviewed / Open Access
• [Presentation] TGF-b works as an essential mediator for RANKL-induced osteoclastogenesis cooperating with c-FOS (2014)
  • Author(s): Yasunori Omata
  • Organizer: JCR summer international school
  • Place of Presentation: Karuizawa, Japan
  • Year and Date: 2014-07-31 – 2014-08-02