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

• Published in: Nature communications Vol. 14; no. 1; p. 23
• Main Authors: Takase, Shohei, Hiroyama, Takashi, Shirai, Fumiyuki, Maemoto, Yuki, Nakata, Akiko, Arata, Mayumi, Matsuoka, Seiji, Sonoda, Takeshi, Niwa, Hideaki, Sato, Shin, Umehara, Takashi, Shirouzu, Mikako, Nishigaya, Yosuke, Sumiya, Tatsunobu, Hashimoto, Noriaki, Namie, Ryosuke, Usui, Masaya, Ohishi, Tomokazu, Ohba, Shun-ichi, Kawada, Manabu, Hayashi, Yoshihiro, Harada, Hironori, Yamaguchi, Tokio, Shinkai, Yoichi, Nakamura, Yukio, Yoshida, Minoru, Ito, Akihiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-01-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 38/15; 38/39; 38/43; 38/47; 38/77; 38/89; 42/41; 45; 45/88; 631/80/458/1648; 631/92/458/1648; 64/60; 64/86; 82/1; 82/103; 96/109; Anemia, Sickle Cell - drug therapy; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - metabolism; Animals; Chemical compounds; Epigenetics; Erythroid cells; Erythroid Cells - metabolism; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; Fetuses; gamma-Globins - genetics; Gene Expression; Genotoxicity; Hemoglobin; Histone deacetylase; Histones; Humanities and Social Sciences; Humans; Hydroxyurea; Inhibitors; Mice; Modulators; Molecular modelling; multidisciplinary; Mutation; Non-coding RNA; NuRD protein; Pharmacology; Repressors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Sickle cell disease
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35404-0

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.
This study describes RK-701, an inhibitor of histone methyltransferases G9a/GLP, as a promising therapeutic candidate for sickle cell disease and a universal role of BGLT3 lncRNA in fetal hemoglobin reactivation by chemical inducers including RK-701.