Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A
Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A
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DOI：
10.1073/pnas.1303976110
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发表时间：
2013-04-16
影响因子：
11.1
通讯作者：
Orkin, Stuart H.
中科院分区：
文献类型：
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作者：
Xu, Jian;Bauer, Daniel E.;Orkin, Stuart H.
胎儿血红蛋白（HbF）在成人中的重新激活可改善常见β-珠蛋白疾病的严重程度。转录因子BCL 11 A是血红蛋白转换和HbF沉默的关键调节剂，但BCL 11 A协调发育转换的分子机制尚不完全清楚。特别是，BCL 11 A合作蛋白复合物的身份及其在HbF表达和红系发育中的作用在很大程度上仍然未知。在这里，我们确定的相互作用的合作伙伴蛋白BCL 11 A在红系细胞的蛋白质组学筛选。BCL 11 A存在于由红细胞转录因子、转录辅阻遏物和染色质修饰酶组成的多蛋白复合物中。我们发现，赖氨酸特异性去甲基化酶1和阻遏元件-1沉默转录因子辅阻遏物1（LSD 1/CoREST）组蛋白去甲基化酶复合物与BCL 11 A相互作用，并需要在体内完全发育沉默小鼠胚胎β-样珠蛋白基因和成人红系细胞中的人γ-珠蛋白基因。此外，LSD 1对正常红细胞发育至关重要。此外，DNA甲基转移酶1（DNMT 1）在蛋白质组学筛选中被鉴定为BCL 11 A相关蛋白。DNMT 1是维持原代人成人红系细胞中HbF沉默所必需的。DNMT 1单倍不足结合BCL 11 A缺陷进一步增强成年动物中γ-珠蛋白的表达。我们的研究结果为BCL 11 A在HbF沉默中的机制作用提供了重要的见解，并为BCL 11 A在β-血红蛋白病中的治疗靶向提供了线索。
Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common beta-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatin-modifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic beta-like globin genes and human gamma-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances gamma-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in beta-hemoglobinopathies.