A promoter DNA demethylation landscape of human hematopoietic differentiation.
A promoter DNA demethylation landscape of human hematopoietic differentiation.
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DOI：
10.1093/nar/gkr685
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发表时间：
2012-01
影响因子：
14.9
通讯作者：
Fraga MF
中科院分区：
文献类型：
--
作者：
Calvanese V;Fernández AF;Urdinguio RG;Suárez-Alvarez B;Mangas C;Pérez-García V;Bueno C;Montes R;Ramos-Mejía V;Martínez-Camblor P;Ferrero C;Assenov Y;Bock C;Menendez P;Carrera AC;Lopez-Larrea C;Fraga MF
定义特定于造血的基因表达程序的全球机制仍不完全清楚。在这里，我们证明了启动子DNA去甲基化与造血特异性基因的激活有关。利用全基因组启动子甲基化阵列，我们在人类胚胎干细胞中发现了694个受启动子DNA甲基化抑制的造血特异性基因，这些基因的甲基化缺失可能与基因表达有关。研究了CD45、CD34、CD28、CD19、T细胞受体(TCR)、MHC-II类基因HLA-DR、穿孔素1和磷脂酰肌醇3-激酶(PI3K)等多个造血特异性基因的启动子甲基化与基因表达之间的关系，结果表明DNA去甲基化并不总是足以激活基因。启动子去甲基化发生在胚胎发育早期或后来的造血细胞分化过程中。对体细胞CD34+HSPC诱导多能干细胞(IPSCs)和CD34+HSPC分化衍生物的全基因组启动子甲基化状态的分析证实了DNA甲基化在调节血液免疫系统基因表达中的作用，并表明这些基因的启动子甲基化可能与茎的形成有关。综上所述，这些数据表明，启动子DNA去甲基化可能在造血室内组织/细胞特定基因组范围的基因调控中发挥作用。
Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34+ HSPCs and differentiated derivatives from CD34+ HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.
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