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

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

  • Nat Commun. 2023 Jan 12;14(1):23. doi: 10.1038/s41467-022-35404-0.
Shohei Takase 1,  Takashi Hiroyama 2,  Fumiyuki Shirai 3,  Yuki Maemoto 1,  Akiko Nakata 4,  Mayumi Arata 5,  Seiji Matsuoka 4,  Takeshi Sonoda 4,  Hideaki Niwa 6,  Shin Sato 6,  Takashi Umehara 6,  Mikako Shirouzu 6,  Yosuke Nishigaya 7,  Tatsunobu Sumiya 7,  Noriaki Hashimoto 7,  Ryosuke Namie 7,  Masaya Usui 8,  Tomokazu Ohishi 9,  Shun-Ichi Ohba 9,  Manabu Kawada 9,  Yoshihiro Hayashi 10,  Hironori Harada 10,  Tokio Yamaguchi 11,  Yoichi Shinkai 12,  Yukio Nakamura 2,  Minoru Yoshida 13 14 15,  Akihiro Ito 16 17
Affiliations

Affiliations

  • 1 Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • 2 Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki, 305-0074, Japan.
  • 3 Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.
  • 4 Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.
  • 5 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.
  • 6 Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, 230-0045, Japan.
  • 7 Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., Shimotsuga-gun, Tochigi, 329-0114, Japan.
  • 8 Support Unit for Bio-Material Analysis, Research Resources Division, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
  • 9 Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Shizuoka, 410-0301, Japan.
  • 10 Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
  • 11 RIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama, Kanagawa, 230-0045, Japan.
  • 12 Cellular Memory Laboratory, Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan.
  • 13 Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan. yoshidam@riken.jp.
  • 14 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan. yoshidam@riken.jp.
  • 15 Department of Biotechnology, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan. yoshidam@riken.jp.
  • 16 Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan. aito@toyaku.ac.jp.
  • 17 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan. aito@toyaku.ac.jp.
PMID: 36635268 DOI: 10.1038/s41467-022-35404-0
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.

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