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

Shohei Takase, Takashi Hiroyama, Fumiyuki Shirai, Yuki Maemoto, Akiko Nakata, Mayumi Arata, Seiji Matsuoka, Takeshi Sonoda, Hideaki Niwa, Shin Sato, Takashi Umehara, Mikako Shirouzu, Yosuke Nishigaya, Tatsunobu Sumiya, Noriaki Hashimoto, Ryosuke Namie, Masaya Usui, Tomokazu Ohishi, Shun-ichi Ohba, Manabu Kawada, Yoshihiro Hayashi, Hironori Harada, Tokio Yamaguchi, Yoichi Shinkai, Yukio Nakamura, Minoru Yoshida () and Akihiro Ito ()
Additional contact information
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
Akihiro Ito: Tokyo University of Pharmacy and Life Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35404-0

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