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A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression

Author

Listed:
  • Shohei Takase

    (Tokyo University of Pharmacy and Life Sciences)

  • Takashi Hiroyama

    (RIKEN BioResource Research Center)

  • Fumiyuki Shirai

    (RIKEN Center for Sustainable Resource Science)

  • Yuki Maemoto

    (Tokyo University of Pharmacy and Life Sciences)

  • Akiko Nakata

    (RIKEN Center for Sustainable Resource Science)

  • Mayumi Arata

    (RIKEN Center for Sustainable Resource Science)

  • Seiji Matsuoka

    (RIKEN Center for Sustainable Resource Science)

  • Takeshi Sonoda

    (RIKEN Center for Sustainable Resource Science)

  • Hideaki Niwa

    (RIKEN Center for Biosystems Dynamics Research)

  • Shin Sato

    (RIKEN Center for Biosystems Dynamics Research)

  • Takashi Umehara

    (RIKEN Center for Biosystems Dynamics Research)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research)

  • Yosuke Nishigaya

    (Kyorin Pharmaceutical Co. Ltd.)

  • Tatsunobu Sumiya

    (Kyorin Pharmaceutical Co. Ltd.)

  • Noriaki Hashimoto

    (Kyorin Pharmaceutical Co. Ltd.)

  • Ryosuke Namie

    (Kyorin Pharmaceutical Co. Ltd.)

  • Masaya Usui

    (RIKEN Center for Brain Science)

  • Tomokazu Ohishi

    (Numazu, Microbial Chemistry Research Foundation)

  • Shun-ichi Ohba

    (Numazu, Microbial Chemistry Research Foundation)

  • Manabu Kawada

    (Numazu, Microbial Chemistry Research Foundation)

  • Yoshihiro Hayashi

    (Tokyo University of Pharmacy and Life Sciences)

  • Hironori Harada

    (Tokyo University of Pharmacy and Life Sciences)

  • Tokio Yamaguchi

    (RIKEN Program for Drug Discovery and Medical Technology Platforms)

  • Yoichi Shinkai

    (Cluster for Pioneering Research)

  • Yukio Nakamura

    (RIKEN BioResource Research Center)

  • Minoru Yoshida

    (RIKEN Center for Sustainable Resource Science
    RIKEN Center for Sustainable Resource Science
    the University of Tokyo)

  • Akihiro Ito

    (Tokyo University of Pharmacy and Life Sciences
    RIKEN Center for Sustainable Resource Science)

Abstract

Sickle cell disease (SCD) is a heritable disorder caused by β-globin gene mutations. Induction of fetal γ-globin is an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as therapeutic agents. However, the molecular mechanisms whereby these small molecules reactivate γ-globin remain unclear. Here we report the development of a highly selective and non-genotoxic G9a inhibitor, RK-701. RK-701 treatment induces fetal globin expression both in human erythroid cells and in mice. Using RK-701, we find that BGLT3 long non-coding RNA plays an essential role in γ-globin induction. RK-701 selectively upregulates BGLT3 by inhibiting the recruitment of two major γ-globin repressors in complex with G9a onto the BGLT3 gene locus through CHD4, a component of the NuRD complex. Remarkably, BGLT3 is indispensable for γ-globin induction by not only RK-701 but also hydroxyurea and other inducers. The universal role of BGLT3 in γ-globin induction suggests its importance in SCD treatment.

Suggested Citation

  • Shohei Takase & Takashi Hiroyama & Fumiyuki Shirai & Yuki Maemoto & Akiko Nakata & Mayumi Arata & Seiji Matsuoka & Takeshi Sonoda & Hideaki Niwa & Shin Sato & Takashi Umehara & Mikako Shirouzu & Yosuk, 2023. "A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35404-0
    DOI: 10.1038/s41467-022-35404-0
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    References listed on IDEAS

    as
    1. Xue-Song Liu & Gurushankar Chandramouly & Emilie Rass & Yinghua Guan & Guocan Wang & Robin M. Hobbs & Anbazhagan Rajendran & Anyong Xie & Jagesh V. Shah & Anthony J. Davis & Ralph Scully & Andrea Luna, 2015. "LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    2. Abdellah Allali-Hassani & Magdalena M. Szewczyk & Danton Ivanochko & Shawna L. Organ & Jabez Bok & Jessica Sook Yuin Ho & Florence P. H. Gay & Fengling Li & Levi Blazer & Mohammad S. Eram & Levon Hala, 2019. "Discovery of a chemical probe for PRDM9," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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