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Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia.
The FEBS Journal ( IF 5.5 ) Pub Date : 2019-10-09 , DOI: 10.1111/febs.15086 Stefania Scalea 1 , Carmen Maresca 2 , Caterina Catalanotto 3 , Rachele Marino 3 , Carlo Cogoni 3 , Anna Reale 1 , Michele Zampieri 1 , Giuseppe Zardo 1
The FEBS Journal ( IF 5.5 ) Pub Date : 2019-10-09 , DOI: 10.1111/febs.15086 Stefania Scalea 1 , Carmen Maresca 2 , Caterina Catalanotto 3 , Rachele Marino 3 , Carlo Cogoni 3 , Anna Reale 1 , Michele Zampieri 1 , Giuseppe Zardo 1
Affiliation
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The 'instructive model' of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation. To provide insight into these conflicting findings, we generated DNA methylation profiles for acute myeloid leukemia samples from patients and leukemic cell lines and integrated them with publicly available ChIp-seq data, containing H3K4me3 and H3K27me3 CpG island occupation in hESC, or hematopoietic stem or progenitor cells (hHSC/MPP). Hypermethylated CpG islands in AML samples displayed H3K27me3 enrichments in hESC and hHSC/MPP; however, ChIp analysis of specific hypermethylated CpG islands revealed a significant reduction in H3K4me3 signal with a concomitant increase in H3K4me0 levels as opposed to a nonsignificant increase in H3K27me3 marks. The integration of AML DNA methylation profiles with the ChIp-seq data in hESC and hHSC/MPP also led to the identification of Iroquois homeobox 2 (IRX2) as a previously unknown factor promoting differentiation of leukemic cells. Our results indicate that in contrast to the 'instructive model', H3K4me3 levels are strongly associated with DNA methylation patterns in AML and have a role in the regulation of critical genes, such as the putative tumor suppressor IRX2.
中文翻译：
H3K4甲基化水平的改变与急性髓细胞性白血病中DNA超甲基化有关。
人类肿瘤中异常DNA甲基化的“指导模型”基于以下观察结果：在癌症中倾向于高甲基化的CpG岛嵌入人类胚胎干细胞（hESC）中富含H3K27me3的染色质中。最近的研究还将CpG岛的甲基化与H3K4的甲基化状态相关联，其中H3K4me3与DNA甲基化呈负相关。为了提供对这些矛盾发现的见解，我们从患者和白血病细胞系中生成了急性髓细胞性白血病样本的DNA甲基化图谱，并将其与公开可用的ChIp-seq数据整合，这些数据包含hESC或造血干细胞或祖细胞中的H3K4me3和H3K27me3 CpG岛占领情况。单元格（hHSC / MPP）。AML样品中的超甲基化CpG岛在hESC和hHSC / MPP中显示H3K27me3富集；然而，对特定的高甲基化CpG岛的ChIp分析显示，H3K4me3信号显着降低，同时H3K4me0水平随之升高，而H3K27me3标记则无明显升高。AML DNA甲基化配置文件与hESC和hHSC / MPP中的ChIp-seq数据的整合还导致易洛魁人同源盒2（IRX2）的鉴定是促进白血病细胞分化的未知因子。我们的结果表明，与“指导性模型”相反，H3K4me3水平与AML中的DNA甲基化模式密切相关，并在关键基因（例如推定的肿瘤抑制因子IRX2）的调节中起作用。
更新日期：2020-03-16
中文翻译：
H3K4甲基化水平的改变与急性髓细胞性白血病中DNA超甲基化有关。
人类肿瘤中异常DNA甲基化的“指导模型”基于以下观察结果：在癌症中倾向于高甲基化的CpG岛嵌入人类胚胎干细胞（hESC）中富含H3K27me3的染色质中。最近的研究还将CpG岛的甲基化与H3K4的甲基化状态相关联，其中H3K4me3与DNA甲基化呈负相关。为了提供对这些矛盾发现的见解，我们从患者和白血病细胞系中生成了急性髓细胞性白血病样本的DNA甲基化图谱，并将其与公开可用的ChIp-seq数据整合，这些数据包含hESC或造血干细胞或祖细胞中的H3K4me3和H3K27me3 CpG岛占领情况。单元格（hHSC / MPP）。AML样品中的超甲基化CpG岛在hESC和hHSC / MPP中显示H3K27me3富集；然而，对特定的高甲基化CpG岛的ChIp分析显示，H3K4me3信号显着降低，同时H3K4me0水平随之升高，而H3K27me3标记则无明显升高。AML DNA甲基化配置文件与hESC和hHSC / MPP中的ChIp-seq数据的整合还导致易洛魁人同源盒2（IRX2）的鉴定是促进白血病细胞分化的未知因子。我们的结果表明，与“指导性模型”相反，H3K4me3水平与AML中的DNA甲基化模式密切相关，并在关键基因（例如推定的肿瘤抑制因子IRX2）的调节中起作用。
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