Epigenetic activities in erythroid cell gene regulation.

Epigenetic activities in erythroid cell gene regulation.
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DOI:
10.1053/j.seminhematol.2020.11.007
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发表时间:
2021-01
影响因子:
3.6
通讯作者:
Singh SA
Singh SA
中科院分区:
医学3区
文献类型:
--
作者:
Wang Y;Yu L;Engel JD;Singh SA

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在过去的几十年里,对表观遗传机制在人类生物学中的作用的兴趣呈指数增长。大量对立的和上下文依赖的染色质修饰酶/共调节复合物才刚刚开始在分子水平上被理解。这门科学极大地受益于红细胞生成的研究,其中一系列β-珠蛋白基因按顺序“打开”和“关闭”,作为协调基因表达的迷人模型。因此,我们在这里描述我们最了解的表观遗传复合物,使用红细胞生成作为背景。这些生化见解为提出和开发红细胞疾病和红细胞生成疾病的新疗法奠定了基础,例如,确定了可以通过药物操纵β-珠蛋白位点调控的表观遗传酶,从而有利于激活未突变的胎儿血红蛋白,而不是突变的成人β-珠蛋白基因,以治疗镰状细胞病和β-地中海贫血。其他潜在的转化应用是在重定向造血承诺的决定,作为治疗骨髓衰竭综合征。
Interest in the role of epigenetic mechanisms in human biology has exponentially increased over the past several decades. The multitude of opposing and context-dependent chromatin-modifying enzymes/coregulator complexes is just beginning to be understood at a molecular level. This science has benefitted tremendously from studies of erythropoiesis, in which a series of β-globin genes are in sequence turned ‘on’ and ‘off’, serving as a fascinating model of coordinated gene expression. We therefore describe here epigenetic complexes about which we know most, using erythropoiesis as the context. The biochemical insights lay the foundation for proposing and developing novel treatments for diseases of red cells and of erythropoiesis, identifying for example epigenetic enzymes that can be drugged to manipulate β-globin locus regulation, to favor activation of unmutated fetal hemoglobin over mutated adult β-globin genes to treat sickle cell disease and β-thalassemias. Other potential translational applications are in redirecting hematopoietic commitment decisions, as treatment for bone marrow failure syndromes.
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