Q1 · CROSS-FIELD
ArticleOA
Author: Maemoto, Yuki ; Hayashi, Yoshihiro ; Shirouzu, Mikako ; Umehara, Takashi ; Niwa, Hideaki ; Sumiya, Tatsunobu ; Ohishi, Tomokazu ; Nakata, Akiko ; Hiroyama, Takashi ; Takase, Shohei ; Usui, Masaya ; Nishigaya, Yosuke ; Shinkai, Yoichi ; Hashimoto, Noriaki ; Namie, Ryosuke ; Shirai, Fumiyuki ; Kawada, Manabu ; Arata, Mayumi ; Sonoda, Takeshi ; Ito, Akihiro ; Sato, Shin ; Yoshida, Minoru ; Matsuoka, Seiji ; Harada, Hironori ; Yamaguchi, Tokio ; Ohba, Shun-Ichi ; Nakamura, Yukio
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.