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.

镰状细胞病 (SCD) 是由 β-珠蛋白基因突变引起的遗传性疾病。胎儿 γ-珠蛋白的诱导是一种既定的治疗策略。最近，表观遗传调节剂，包括 G9a 抑制剂，已被提议作为治疗剂。然而，这些小分子重新激活 γ-珠蛋白的分子机制仍不清楚。在这里，我们报告了一种高选择性和非遗传毒性的 G9a 抑制剂 RK-701 的开发。RK-701 治疗可诱导人红细胞和小鼠中的胎儿珠蛋白表达。使用 RK-701，我们发现 BGLT3 长链非编码 RNA 在 γ-珠蛋白诱导中起着重要作用。RK-701 通过抑制与 G9a 复合的两种主要 γ-珠蛋白阻遏物通过 CHD4（NuRD 复合体的一个组成部分）募集到 BGLT3 基因座上，从而选择性上调 BGLT3。值得注意的是，BGLT3 对于 RK-701 以及羟基脲和其他诱导剂的 γ-珠蛋白诱导都是必不可少的。BGLT3 在 γ 珠蛋白诱导中的普遍作用表明其在 SCD 治疗中的重要性。