Sex spectrum defined by sex chromosomal heterochromatin

• Project Area: Spectrum of the Sex: a continuity of phenotypes between female and male
• Project/Area Number: 17H06426
• 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: Osaka University
• Principal Investigator: Nagao Koji 大阪大学, 大学院理学研究科, 准教授 (60426575)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥106,210,000 (Direct Cost: ¥81,700,000、Indirect Cost: ¥24,510,000); Fiscal Year 2021: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2020: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2019: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2018: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2017: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000)
• Keywords: 性スペクトラム / エピジェネティクス / X染色体不活性化 / 性スぺクトラム

Outline of Final Research Achievements

To understand the sex spectrum, it is necessary to capture the smallest element of the sex spectrum establishment, which is defined by genetic factors in each cell. To elucidate the mechanism of the sex spectrum defined by sex chromosome heterochromatin, we clarified the role of SMCHD1 required for the heterochromatin structure of the inactive X chromosome. SMCHD1 is essential for the stable silencing of the inactive X chromosome during embryonic differentiation and the formation of repressive histone modification patterns across the inactive X chromosome.

Academic Significance and Societal Importance of the Research Achievements

哺乳類では、雌雄間で数が異なるX染色体上の遺伝子量を補償するため、雌では2本あるX染色体のうちの一方のX染色体では、遺伝子発現が発生のごく初期から染色体全域に渡って不活性化されます。このため女性の体細胞には、男性と異なり巨大なヘテロクロマチンである不活性X染色体が保持されているという特徴があります。そのため、不活性X染色体が構築され、維持される仕組みや、不活性X染色体が核内の他の遺伝子に与える影響への理解が進むことで、女性に偏る疾患の予防・治療へと繋がります。

Research Products

• [Journal Article] Polycomb repressive complexes 1 and 2 are each essential for maintenance of X inactivation in extra-embryonic lineages (2023)
  • Author(s): Masui Osamu、Corbel Catherine、Nagao Koji、Endo Takaho A.、Kezuka Fuyuko、Diabangouaya Patricia、Nakayama Manabu、Kumon Mami、Koseki Yoko、Obuse Chikashi、Koseki Haruhiko、Heard Edith
  • Journal Title: Nature Cell Biology Volume: 25 Issue: 1 Pages: 134-144
  • DOI: 10.1038/s41556-022-01047-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice (2022)
  • Author(s): Ichihara Saya、Nagao Koji、Sakaguchi Takehisa、Obuse Chikashi、Sado Takashi
  • Journal Title: Development Volume: 149 Issue: 15
  • DOI: 10.1242/dev.200864
  • Peer Reviewed / Open Access
• [Journal Article] RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells (2022)
  • Author(s): Sugawara S, Okada R, Loo TM, Tanaka H, Miyata K, Chiba M, Kawasaki H, Katoh K, Kaji S, Maezawa Y, Yokote K, Nakayama M, Oshima M, Nagao K, Obuse C, Nagayama S, Takubo K, Nakanishi A, Kanemaki MT, Hara E, Takahashi A.
  • Journal Title: Commun Biol Volume: 5 Issue: 1 Pages: 1420-1420
  • DOI: 10.1038/s42003-022-04369-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action (2021)
  • Author(s): Isobe Shin-Ya、Hiraga Shin-ichiro、Nagao Koji、Sasanuma Hiroyuki、Donaldson Anne D.、Obuse Chikashi
  • Journal Title: Cell Reports Volume: 36 Issue: 2 Pages: 109383-109383
  • DOI: 10.1016/j.celrep.2021.109383
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asymmetrical localization of Nup107-160 subcomplex components within the nuclear pore complex in fission yeast (2019)
  • Author(s): Asakawa Haruhiko、Kojidani Tomoko、Yang Hui-Ju、Ohtsuki Chizuru、Osakada Hiroko、Matsuda Atsushi、Iwamoto Masaaki、Chikashige Yuji、Nagao Koji、Obuse Chikashi、Hiraoka Yasushi、Haraguchi Tokuko
  • Journal Title: PLOS Genetics Volume: 15 Issue: 6 Pages: 008061-1008061
  • DOI: 10.1371/journal.pgen.1008061
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide stability of the DNA replication program in single mammalian cells (2019)
  • Author(s): Saori Takahashi, Hisashi Miura, Takahiro Shibata, Koji Nagao, Katsuzumi Okumura, Masato Ogata, Chikashi Obuse, Shin-ichiro Takebayashi and Ichiro Hiratani
  • Journal Title: Nature Genetics Volume: 51 Issue: 3 Pages: 529-540
  • DOI: 10.1038/s41588-019-0347-5
  • Peer Reviewed / Open Access
• [Journal Article] Role of SmcHD1 in establishment of epigenetic states required for the maintenance of the X-inactivated state in mice (2018)
  • Author(s): Sakakibara Yuki、Nagao Koji、Blewitt Marnie、Sasaki Hiroyuki、Obuse Chikashi、Sado Takashi
  • Journal Title: Development Volume: 145 Issue: 18 Pages: 806-821
  • DOI: 10.1242/dev.166462
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nucleosomes around a mismatched base pair are excluded via an Msh2-dependent reaction with the aid of SNF2 family ATPase Smarcad1. (2018)
  • Author(s): Terui R, Nagao K, Kawasoe Y, Taki K, Higashi TL, Tanaka S, Nakagawa T, Obuse C, Masukata H, Takahashi TS
  • Journal Title: Genes & development Volume: 32(11-12) Issue: 11-12 Pages: 806-821
  • DOI: 10.1101/gad.310995.117
  • Peer Reviewed / Open Access
• [Journal Article] Defects in dosage compensation impact global gene regulation in the mouse trophoblast (2017)
  • Author(s): Sakata Yuka、Nagao Koji、Hoki Yuko、Sasaki Hiroyuki、Obuse Chikashi、Sado Takashi
  • Journal Title: Development Volume: 144 Issue: 15 Pages: 2784-2797
  • DOI: 10.1242/dev.149138
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of RIF1 by SCAI Allows BRCA1-Mediated Repair. (2017)
  • Author(s): Isobe S.Y., Nagao K., Nozaki N., Kimura H., and Obuse C.
  • Journal Title: Cell Rep. Volume: 2 Issue: 2 Pages: 297-307
  • DOI: 10.1016/j.celrep.2017.06.056
  • Peer Reviewed / Open Access
• [Journal Article] Exosomes maintain cellular homeostasis by excreting harmful DNA from cells (2017)
  • Author(s): Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M.T., Obuse, C. & Hara, E.
  • Journal Title: Nature Communications Volume: - Issue: 1 Pages: 15287-15287
  • DOI: 10.1038/ncomms15287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in ciliate Tetrahymena. (2017)
  • Author(s): Iwamoto M., Osakada H., Mori C., Fukuda Y., Nagao K., Obuse C., Hiraoka Y., and Haraguchi T.
  • Journal Title: J Cell Sci. Volume: 印刷中 Issue: 10 Pages: 1822-1834
  • DOI: 10.1242/jcs.199398
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Smchd1-Hbix1依存的な不活性化 X染色体の区画化 (2018)
  • Author(s): 長尾恒治、榊原祐樹、柴田幸子、野澤竜介、坂口武久、木村宏、佐渡敬、小布施力史
  • Organizer: 第４１回日本分子生物学会年会
• [Presentation] Smchd1-Hbix1依存的な不活性化 X染色体の区画化 (2018)
  • Author(s): 長尾恒治
  • Organizer: 第６回 X染色体研究会
• [Presentation] Smchd1-Hbix1依存的な不活性化 X染色体の区画化 (2017)
  • Author(s): 長尾恒治、榊原祐樹、柴田幸子、野澤竜介、元田裕佳里、坂口武久、木村宏、佐渡敬、小布施力史
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] Smchd1-Hbix1依存的な不活性化X染色体の区画化 (2017)
  • Author(s): 長尾恒治
  • Organizer: 第5回 X染色体研究会