Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada.
Departments of Biochemistry and Chemistry, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada.
Cell Stem Cell. 2021 Jan 7;28(1):48-62.e6. doi: 10.1016/j.stem.2020.12.002.
Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacity when cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, most notably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylase LSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulates the CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activity of UM171. The mechanism underlying the UM171-mediated loss of CoREST function remains undetermined. We now report that UM171 potentiates the activity of a CULLIN3-E3 ubiquitin ligase (CRL3) complex whose target specificity is dictated by the poorly characterized Kelch/BTB domain protein KBTBD4. CRL3 targets components of the LSD1/RCOR1 corepressor complex for proteasomal degradation, hence re-establishing H3K4me2 and H3K27ac epigenetic marks, which are rapidly decreased upon ex vivo culture of human HSCs.
人类造血干细胞（HSCs）在体外培养时会表现出自我更新能力的损耗，这一过程在经过表观遗传修饰剂（尤其是组蛋白去乙酰化酶[HDAC]抑制剂或赖氨酸特异性去甲基化酶 LSD1 抑制剂）处理后部分逆转。最近的一项研究表明，人类 HSC 自我更新激动剂 UM171 调节 CoREST 复合物，导致 LSD1 降解，其抑制作用模拟了 UM171 的活性。UM171 介导的 CoREST 功能丧失的机制尚不清楚。我们现在报告称，UM171 增强了 CULLIN3-E3 泛素连接酶（CRL3）复合物的活性，该复合物的靶标特异性由特征不明显的 Kelch/BTB 结构域蛋白 KBTBD4 决定。CRL3 靶向 LSD1/RCOR1 核心抑制复合物的组件进行蛋白酶体降解，从而重新建立 H3K4me2 和 H3K27ac 表观遗传标记，这些标记在人类 HSCs 体外培养时会迅速减少。
