Department of Hematology.
Department of Structural Biology.
Blood. 2021 Jan 14;137(2):155-167. doi: 10.1182/blood.2020007809.
The histone mark H3K27me3 and its reader/writer polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for hematopoietic development but are poorly understood. Here we show that the E3 ubiquitin ligase F-box only protein 11 (FBXO11) relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate bromo adjacent homology domain-containing 1 (BAHD1), an H3K27me3 reader that recruits transcriptional corepressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks at their promoters. In FBXO11-/- erythroblasts, these gene promoters bind BAHD1 and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2, and depletion of either component restores FBXO11-deficient erythroid gene expression. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at many developmentally poised bivalent genes during erythropoiesis.
组蛋白标记 H3K27me3 及其读取器/写入器多梳抑制复合物 2（PRC2）在干细胞和祖细胞中介导广泛的转录抑制。调节这种活性的机制对于造血发育至关重要，但了解甚少。在这里，我们表明 E3 泛素连接酶 F-box 仅蛋白 11（FBXO11）通过靶向其新鉴定的底物溴相邻同源结构域包含 1（BAHD1）来缓解红细胞成熟过程中 PRC2 介导的抑制，BAHD1 是一种 H3K27me3 读取器，可招募转录共抑制因子。缺乏 FBXO11 的红细胞发育迟缓，成熟相关基因的表达减少，其中大多数基因在其启动子处具有双价组蛋白标记。在 FBXO11-/-红细胞中，这些基因启动子与 BAHD1 结合，并且不能募集红细胞转录因子 GATA1。BAHD1 复合物与 PRC2 物理相互作用，并且两种成分的耗竭都可以恢复 FBXO11 缺陷型红细胞基因的表达。我们的研究将 BAHD1 鉴定为 PRC2 介导的抑制的新型效应因子，并揭示了单个 E3 泛素连接酶如何在红细胞生成过程中消除许多处于发育状态的双价基因中的 PRC2 抑制。
