Epigenetic changes during hematopoietic cell granulocytic differentiation--comparative analysis of primary CD34+ cells, KG1 myeloid cells and mature neutrophils.
Epigenetic changes during hematopoietic cell granulocytic differentiation--comparative analysis of primary CD34+ cells, KG1 myeloid cells and mature neutrophils.
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DOI：
10.1186/1471-2121-15-4
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发表时间：
2014-01-20
期刊：
影响因子：
--
通讯作者：
Magnusson KE
中科院分区：
文献类型：
--
作者：
Navakauskienė R;Borutinskaitė VV;Treigytė G;Savickienė J;Matuzevičius D;Navakauskas D;Magnusson KE
表观遗传调控是已知的影响基因表达的因素，最近的研究表明DNA甲基化模式异常和组蛋白修饰可能在白血病的发生中起作用。为了强调在后一过程中起作用的表观遗传机制的协同作用，重要的是阐明它们作为粒细胞分化的生物标志物的潜力。在这项研究中，我们研究了人类造血细胞在不同分化阶段的表观遗传学变化：原始造血细胞CD34+细胞，发育停止在分化早期的KG1髓系白血病细胞，以及成熟的中性粒细胞。我们重点介绍了细胞周期调控基因(p15、p16)和分化相关基因(E-钙粘素和RARβ)的表观遗传状态。我们发现，其中一些基因启动子区的甲基化水平在KG1细胞中相当高，而在CD34+细胞和人中性粒细胞中较低。通过计算机辅助方法检测和评估，组蛋白H3和H4的修饰，即H3K4me3，H3K9Ac，H3K9Ac/S10Ph和H4HyperAc，在CD34+细胞和人成熟中性粒细胞中是相似的。相反，在KG1细胞中，组蛋白H3和H4的修饰相当高，并且在HDAC抑制剂苯丁酸酯诱导粒细胞分化后增加。我们发现被检测的基因启动子和组蛋白修饰的甲基化状态与造血细胞的祖细胞状态有关，这种状态被诱导分化为髓系KG1细胞和正常的血液中性粒细胞。这可以通过对β甲基化/去甲基化引起的E-钙粘蛋白、p15、p16和RAR基因表达的表观遗传调控，核心和连接组蛋白在干细胞中的分布，诱导KG1细胞和成熟的中性粒细胞分化，以及组蛋白修饰H3K4me3，H3K9Ac，H3K9Ac/S10Ph和H4 HyperAc与造血细胞向粒细胞分化有关。这些发现也提示它们可能是造血细胞粒细胞分化的潜在重要生物标志物，并可能对白血病诱导分化治疗有价值。
Epigenetic regulation is known to affect gene expression, and recent research shows that aberrant DNA methylation patterning and histone modifications may play a role in leukemogenesis. In order to highlight the co-operation of epigenetic mechanisms acting during the latter process it is important to clarify their potential as biomarkers of granulocytic differentiation. In this study we investigated epigenetic alterations in human hematopoietic cells at a distinct differentiation stages: primary hematopoietic CD34+ cells, KG1 myeloid leukemic cells, whose development is stopped at early stage of differentiation, and mature neutrophils. We focused on the epigenetic status of cell cycle regulating (p15, p16) and differentiation related (E-cadherin and RARβ) genes. We found that the methylation level in promoter regions of some of these genes was considerably higher in KG1 cells and lower in CD34+ cells and human neutrophils. As examined and evaluated by computer-assisted methods, histone H3 and H4 modifications, i.e. H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc, were similar in CD34+ cells and human mature neutrophils. By contrast, in the KG1 cells, histone H3 and H4 modifications were quite high and increased after induction of granulocytic differentiation with the HDAC inhibitor phenyl butyrate. We found the methylation status of the examined gene promoters and histone modifications to be characteristically associated with the hematopoietic cell progenitor state, induced to differentiate myeloid KG1 cells and normal blood neutrophils. This could be achieved through epigenetic regulation of E-cadherin, p15, p16 and RARβ genes expression caused by DNA methylation/demethylation, core and linker histones distribution in stem hematopoietic cells, induced to differentiation KG1 cells and mature human neutrophils, as well as the histone modifications H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc in relation to hematopoietic cell differentiation to granulocyte. These findings also suggest them as potentially important biomarkers of hematopoietic cell granulocytic differentiation and could be valuable for leukemia induced differentiation therapy.
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影响因子：
8
作者：
Fazi, F;Travaglini, L;Nervi, C
通讯作者：
Nervi, C
影响因子：
3.5
作者：
Galm, O;Wilop, S;Osieka, R
通讯作者：
Osieka, R
影响因子：
2.1
作者：
Melnick, Ari M.
通讯作者：
Melnick, Ari M.
影响因子：
11.4
作者：
DETHE, H;MARCHIO, A;DEJEAN, A
通讯作者：
DEJEAN, A
影响因子：
2.6
作者：
Kusy, S;Larsen, CJ;Roche, J
通讯作者：
Roche, J