Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand.
Genes Dev. 2018 Dec 1;32(23-24):1537-1549. doi: 10.1101/gad.318436.118. Epub 2018 Nov 21.
Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.
人类珠蛋白基因的转录“开关”在出生后不久从胎儿向成人合成转变，由散布在整个基因座中的元件增强子或沉默子来控制。DRED（直接重复红系决定）抑制子通过孤儿核受体 TR2（NR2C1）和 TR4（NR2C2）招募到ε-珠蛋白和γ-珠蛋白启动子，使其在成体红细胞中沉默。在这里，我们发现核受体共抑制因子-1（NCoR1）是 DRED 的一个关键组成部分，它作为一个支架，将 DNA 结合和表观遗传酶成分（如 DNA 甲基转移酶 1 [DNMT1]和赖氨酸特异性去甲基化酶 1 [LSD1]）结合在一起，从而发挥 DRED 的功能。我们还描述了一个新的γ-珠蛋白抑制的有效调节剂：去泛素化酶 BRCA1 相关蛋白-1（BAP1）是抑制复合物的一个组成部分，其活性使 NCoR1 保持在β-珠蛋白基因座的位点上，而在红细胞中抑制 BAP1 会大量诱导γ-珠蛋白的合成。这些数据通过发现新的表观遗传酶来介导γ-珠蛋白基因抑制，提供了新的机制见解。
