Undifferentiated hematopoietic cells are characterized by a genome-wide undermethylation dip around the transcription start site and a hierarchical epigenetic plasticity
Undifferentiated hematopoietic cells are characterized by a genome-wide undermethylation dip around the transcription start site and a hierarchical epigenetic plasticity
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DOI：
10.1182/blood-2009-01-197780
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发表时间：
2009-12-03
期刊：
影响因子：
20.3
通讯作者：
Oh, Il-Hoan
中科院分区：
文献类型：
--
作者：
Chung, Yun Shin;Kim, Hye Joung;Oh, Il-Hoan
有关造血干细胞(HSCs)表观遗传调控的证据越来越多，但HSCs的全基因组表观遗传学特征及其功能意义仍不清楚。在这项研究中，通过对人CD34(+)和CD34(-)细胞中CpG甲基化的全基因组比较，我们发现在未分化的CD34(+)细胞中，在启动子转录起始点附近存在特征性的低甲基化，而在未分化的CD34(+)细胞的侧翼区域存在高甲基化。在与CpG岛(CGI(-))无关的基因中，这种围绕转录起始点的“二价”CpG甲基化模式比CGI(+)基因更为突出。未分化的造血细胞也表现出与活跃转录相关的动态染色质和比终末分化的细胞更高的组蛋白乙酰化转化率。有趣的是，化学处理(5-氮杂胞苷、曲古抑素A)抑制染色质凝聚，可促进重建骨髓中“受刺激”的HSC的自我更新，但不能促进“稳态”HSCs在静止期骨髓中的自我更新。相比之下，对更成熟的细胞进行类似的处理，会在与其造血分化相关的水平上导致部分表型去分化和细胞凋亡。综上所述，我们的研究揭示了造血细胞的未分化状态具有独特的表观遗传学特征，包括动态的染色质结构和与未分化程度相关的表观遗传学可塑性。(血。2009；114：4968-4978)
Evidence for the epigenetic regulation of hematopoietic stem cells (HSCs) is growing, but the genome-wide epigenetic signature of HSCs and its functional significance remain unclear. In this study, from a genome-wide comparison of CpG methylation in human CD34(+) and CD34(-) cells, we identified a characteristic undermethylation dip around the transcription start site of promoters and an overmethylation of flanking regions in undifferentiated CD34(+) cells. This "bivalent-like" CpG methylation pattern around the transcription start site was more prominent in genes not associated with CpG islands (CGI(-)) than CGI(+) genes. Undifferentiated hematopoietic cells also exhibited dynamic chromatin associated with active transcription and a higher turnover of histone acetylation than terminally differentiated cells. Interestingly, inhibition of chromatin condensation by chemical treatment (5-azacytidine, trichostatin A) enhanced the self-renewal of "stimulated" HSCs in reconstituting bone marrows but not "steady-state" HSCs in stationary phase bone marrows. In contrast, similar treatments on more mature cells caused partial phenotypic dedifferentiation and apoptosis at levels correlated with their hematopoietic differentiation. Taken together, our study reveals that the undifferentiated state of hematopoietic cells is characterized by a unique epigenetic signature, which includes dynamic chromatin structures and an epigenetic plasticity that correlates to level of undifferentiation. (Blood. 2009; 114: 4968-4978)