Epigenomic changes during leukemia cell differentiation: Analysis of histone acetylation and cytosine methylation using CpG island microarrays
Epigenomic changes during leukemia cell differentiation: Analysis of histone acetylation and cytosine methylation using CpG island microarrays
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DOI：
10.1124/jpet.104.072488
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Futscher, BW
中科院分区：
文献类型：
--
作者：
Nouzova, M;Holtan, N;Futscher, BW
表观遗传调控失调是肿瘤发生的重要参与者。急性早幼粒细胞白血病（APL）中的PML/RAR α易位就是一个例子，由此产生的融合蛋白招募组蛋白去乙酰化酶复合物靶向基因，导致其不适当的转录抑制。全反式维甲酸（ATRA）作为一种配体，减轻了这种抑制，并产生了癌细胞的表观遗传转录重编程。应用CpG岛微阵列技术分析了人APL细胞系NB4与ATRA分化前后及正常外周血单核细胞（PBMC）的DNA甲基化和组蛋白乙酰化状态。与PBMC相比，NB4细胞中已知基因转录起始位点1kb内超过70个CpG岛异常甲基化；然而，atra诱导分化后未检测到胞嘧啶甲基化的变化。关于组蛋白H4乙酰化，在atra诱导分化后，已知人类基因转录起始1kb内超过100个单拷贝CpG岛发生高乙酰化。一个CpG岛在NB4细胞中异常甲基化，但在ATRA治疗后变成高乙酰化并被诱导，并且与HoxA1基因相关，表明它可能是APL中ATRA的靶基因。除了单拷贝序列外，与其他高拷贝序列（如Alu或rDNA）相比，在卫星DNA中检测到选择性乙酰化的增加。总之，ATRA在白血病细胞分化过程中刺激复杂的表观基因组变化，监测这些变化可能有助于发现表观遗传功能障碍的新靶点。
Dysregulation of epigenetic control is an important participant in carcinogenesis. The PML/RAR alpha translocation in acute promyelocytic leukemia (APL) is an example where the resultant fusion protein recruits histone deacetylase complexes to target genes resulting in their inappropriate transcriptional repression. All-trans-retinoic acid ( ATRA) acts as a ligand that relieves this repression and produces an epigenetic transcriptional reprogramming of the cancer cell. CpG island microarrays were used to analyze the DNA methylation and histone acetylation state of the human APL cell line NB4 before and after differentiation with ATRA as well as normal peripheral blood mononuclear cells (PBMC). Over 70 CpG islands within 1 kb of transcription start of a known gene are aberrantly methylated in NB4 cells compared with PBMC; however, no changes in cytosine methylation were detected following ATRA-induced differentiation. With respect to histone H4 acetylation, over 100 single-copy CpG islands within 1 kb of transcription start of a known human gene became hyperacetylated following ATRA-induced differentiation. One CpG island was aberrantly methylated in NB4 cells, but became hyperacetylated and was induced following ATRA treatment and was associated with the HoxA1 gene, suggesting it may be a target gene of ATRA in APL. In addition to single-copy sequences, a selective increase in acetylation was detected in satellite DNA when compared with other high-copy sequences, such as Alu or rDNA. In summary, ATRA stimulates complex epigenomic changes during leukemic cell differentiation, and monitoring these changes may help to identify new targets of epigenetic dysfunction.