The role of the chromatin remodeler Mi-2β in hematopoietic stem cell self-renewal and multilineage differentiation
The role of the chromatin remodeler Mi-2β in hematopoietic stem cell self-renewal and multilineage differentiation
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DOI：
10.1101/gad.1642808
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发表时间：
2008-05-01
影响因子：
10.5
通讯作者：
Georgopoulos, Katia
中科院分区：
文献类型：
--
作者：
Yoshida, Toshimi;Hazan, Idit;Georgopoulos, Katia
体细胞自我更新和分化为下游谱系的能力依赖于特殊的染色质环境，这种环境使干细胞特异性基因保持活跃，关键分化因子受到抑制，但有可能被激活。提供这类调控的表观遗传因素仍不明确。在这里，我们提供了第一个证据，核小体重塑脱乙酰酶(NuRD)复合体的SNF2样ATPase Mi-2β是维持早期造血系统和多系分化所必需的。在Mi-2β条件灭活后不久，在富含HSC(造血干细胞)的骨髓群体中，周期增加，静止减少。这些循环突变细胞很容易分化成红系，但不能分化成髓系和淋巴系。总而言之，这些效应导致突变的HSC和红系祖细胞最初的扩张，随着更多分化的前红系母细胞在表现出红系白血病特征的造血部位聚集，这些细胞后来被耗尽。对突变型HSC基因表达的检测表明，与自我更新和谱系启动相关的基因表达发生了变化，Mi-2β在它们的调节中发挥了关键作用。因此，Mi-2 Beta为造血系统提供了免疫细胞能力以及广泛的再生能力。
The ability of somatic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that keep stem cell-specific genes active and key differentiation factors repressed but poised for activation. The epigenetic factors that provide this type of regulation remain ill-defined. Here we provide the first evidence that the SNF2-like ATPase Mi-2 beta of the Nucleosome Remodeling Deacetylase (NuRD) complex is required for maintenance of and multilineage differentiation in the early hematopoietic hierarchy. Shortly after conditional inactivation of Mi-2 beta, there is an increase in cycling and a decrease in quiescence in an HSC (hematopoietic stem cell)-enriched bone marrow population. These cycling mutant cells readily differentiate into the erythroid lineage but not into the myeloid and lymphoid lineages. Together, these effects result in an initial expansion of mutant HSC and erythroid progenitors that are later depleted as more differentiated proerythroblasts accumulate at hematopoietic sites exhibiting features of erythroid leukemia. Examination of gene expression in the mutant HSC reveals changes in the expression of genes associated with self-renewal and lineage priming and a pivotal role of Mi-2 beta in their regulation. Thus, Mi-2 beta provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity.