An integrative genomic and epigenomic approach for the study of transcriptional regulation.
An integrative genomic and epigenomic approach for the study of transcriptional regulation.
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DOI：
10.1371/journal.pone.0001882
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发表时间：
2008-03-26
期刊：
影响因子：
3.7
通讯作者：
Melnick A
中科院分区：
文献类型：
--
作者：
Figueroa ME;Reimers M;Thompson RF;Ye K;Li Y;Selzer RR;Fridriksson J;Paietta E;Wiernik P;Green RD;Greally JM;Melnick A
急性白血病和其他肿瘤的分子异质性是理解疾病发病机制和开发新的靶向治疗的主要障碍。异常基因调控是癌症的一个标志，在决定肿瘤表型中起着核心作用。我们预测，整合不同的全基因组表观遗传调控标记以及基因表达水平将为捕获白血病亚型之间的生物学差异提供更大的能力。采用高密度寡核苷酸微阵列技术检测原发性人急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）的基因表达、胞嘧啶甲基化和组蛋白H3赖氨酸9 （H3K9）乙酰化。正如预期的那样，我们发现DNA甲基化和H3K9乙酰化区分了这些不同细胞系的白血病，但是结合每个平台的信息进行的综合分析揭示了数百个单独的基因表达阵列所遗漏的额外差异表达基因。这一综合分析也增强了AML和ALL中生物学通路失调的检测和统计学意义。因此，使用临床样本进行综合表观基因组研究是可行的，并且比单平台微阵列研究提供了更好的异常转录编程检测。
The molecular heterogeneity of acute leukemias and other tumors constitutes a major obstacle towards understanding disease pathogenesis and developing new targeted-therapies. Aberrant gene regulation is a hallmark of cancer and plays a central role in determining tumor phenotype. We predicted that integration of different genome-wide epigenetic regulatory marks along with gene expression levels would provide greater power in capturing biological differences between leukemia subtypes. Gene expression, cytosine methylation and histone H3 lysine 9 (H3K9) acetylation were measured using high-density oligonucleotide microarrays in primary human acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) specimens. We found that DNA methylation and H3K9 acetylation distinguished these leukemias of distinct cell lineage, as expected, but that an integrative analysis combining the information from each platform revealed hundreds of additional differentially expressed genes that were missed by gene expression arrays alone. This integrated analysis also enhanced the detection and statistical significance of biological pathways dysregulated in AML and ALL. Integrative epigenomic studies are thus feasible using clinical samples and provide superior detection of aberrant transcriptional programming than single-platform microarray studies.
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