Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes
Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes
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Uhrf1通过表观遗传调节细胞分裂模式来控制造血干细胞的自我更新与分化
DOI：
10.1073/pnas.1612967114
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发表时间：
2017
影响因子：
11.1
通讯作者：
Liu Xiaolong
中科院分区：
文献类型：
--
作者：
Zhao Jingyao;Chen Xufeng;Song Guangrong;Zhang Jiali;Liu Haifeng;Liu Xiaolong
重要意义造血干细胞(HSCs)具有自我更新和分化的能力，以维持所有血细胞的终生生产。然而，单个造血干细胞是如何完成自我更新与分化的决定仍然很大程度上是未知的。在这里，我们发现uhrf1，DNA甲基化的关键表观遗传调节因子，专门控制这一关键过程。在缺乏uhrf1的情况下，造血干细胞以自我更新能力为代价进行红系偏向分化，导致造血衰竭和死亡。在机制上，uhrf1通过DNA甲基化介导抑制某些红系特异性基因的表达来调节HSC的分裂模式，从而调节HSC的细胞命运决定。这项研究为uhrf1介导的DNA甲基化、细胞分裂模式和HSC命运决定之间的关系提供了独特的见解。造血干细胞(HSCs)具有自我更新和分化能力。然而，个体HSC是如何在自我更新和分化之间做出决定的，在很大程度上仍然是未知的。在这里，我们报道，在造血系统中，去除关键的表观遗传调节因子uhrf1会耗尽HSC池，导致造血衰竭和死亡。Uhrf1缺陷的HSC表现出正常的存活和增殖，但以自我更新能力为代价进行红系偏向分化。值得注意的是，在HSC分裂过程中，uhrf1是建立红系特异基因DNA甲基化模式所必需的。在缺乏uhrf1的情况下，这些基因的表达增强，从而通过促进对称分化和抑制对称自我更新来扰乱HSC的分裂模式。此外，其中一个上调基因GATA1在HSCs中的过度表达足以导致uhrf1表型缺陷的HSC，表现为HSC对称性自我更新受损和分化承诺增加。综上所述，我们的研究结果表明，uhrf1通过表观遗传调控细胞分裂模式来控制HSC的自我更新和分化，从而为uhrf1介导的DNA甲基化、细胞分裂模式和HSC命运决定之间的关系提供了独特的见解。
Significance Hematopoietic stem cells (HSCs) harbor the capacities of both self-renewal and differentiation to sustain life-long production of all blood cells. However, how individual HSCs accomplish the decision of self-renewal versus differentiation remains largely unknown. Here, we find that Uhrf1, a key epigenetic regulator of DNA methylation, specifically controls this critical process. In the absence of Uhrf1, HSCs undergo erythroid-biased differentiation at the expense of self-renewal capacity, leading to hematopoietic failure and lethality. Mechanistically, Uhrf1 regulates the HSC-division mode by DNA methylation-mediated repression of the expression of certain erythroid-specific genes, and thus modulates the cell fate decision of HSCs. This study provides unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision. Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.