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
  • 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. [email protected].
  • 14. Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan. [email protected].
  • 15. Department of Biotechnology, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan. [email protected].
  • 16. Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan. [email protected].
  • 17. Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan. [email protected].
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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