Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles.
Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles.
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DOI：
10.1186/1755-8794-8-s2-s6
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发表时间：
2015
影响因子：
2.7
通讯作者：
Cunningham JM
中科院分区：
文献类型：
--
作者：
Yang XH;Wang B;Cunningham JM
与治疗相关的继发性急性髓系白血病(t-AML)是强化化疗的一种日益常见的并发症。这种恶性肿瘤的特征通常是7号染色体的异常，包括大的缺失或染色体丢失。多项研究表明，位于7q36.1的EZH2基因表达降低在疾病发病机制中起关键作用。这个组蛋白甲基转移酶通过修饰赖氨酸27(H3K27)上的组蛋白H3参与转录抑制。然而，EZH2的关键靶基因及其调控作用仍不清楚。为了表征可能与t-AML发病相关的EZH2靶基因的子集，我们开发了一种新的计算分析来整合组织特异性的组蛋白修饰和基因组范围的转录调控。初步的整合分析利用一种新的“seq2基因”策略，大量探索染色质免疫沉淀测序(ChIP-SEQ)富集区的靶基因。通过将seq2基因与我们的表型-基因组-网络(PGNet)算法相结合，我们将具有相似表达谱和基因组或功能特征的基因丰富为“生物模块”。初步研究确定SEMA3A(信号灯3A)是一种新的致癌候选基因，受EZH2沉默调控，使用来自正常和白血病细胞系以及EZH2缺陷小鼠细胞的数据。SEMA3A启动子上的微卫星标记与化疗敏感性和放射敏感性有关。值得注意的是，我们随后对初级t-AML的研究表明，EZH2调节的SEMA3A预期上调。此外，我们还鉴定了三个与SEMA3A共表达并在t-AML中上调的生物模块，其中一个由先前特征的EZH2抑制的基因靶点组成。另外两个生物模块包括MAPK8和TATA盒靶标。总之，我们的研究表明EZH2靶点在t-AML发病机制中的重要作用值得进一步研究。这些开发的计算算法和系统生物学策略将加强对t-AML和其他复杂疾病的多个下一代测序数据的知识发现和假设驱动的分析。
Therapy-related, secondary acute myeloid leukemia (t-AML) is an increasingly frequent complication of intensive chemotherapy. This malignancy is often characterized by abnormalities of chromosome 7, including large deletions or chromosomal loss. A variety of studies suggest that decreased expression of the EZH2 gene located at 7q36.1 is critical in disease pathogenesis. This histone methyltransferase has been implicated in transcriptional repression through modifying histone H3 on lysine 27 (H3k27). However, the critical target genes of EZH2 and their regulatory roles remain unclear. To characterize the subset of EZH2 target genes that might contribute to t-AML pathogenesis, we developed a novel computational analysis to integrate tissue-specific histone modifications and genome-wide transcriptional regulation. Initial integrative analysis utilized a novel "seq2gene" strategy to explore largely the target genes of chromatin immuneprecipitation sequencing (ChIP-seq) enriched regions. By combining seq2gene with our Phenotype-Genotype-Network (PGNet) algorithm, we enriched genes with similar expression profiles and genomic or functional characteristics into "biomodules". Initial studies identified SEMA3A (semaphoring 3A) as a novel oncogenic candidate that is regulated by EZH2-silencing, using data derived from both normal and leukemic cell lines as well as murine cells deficient in EZH2. A microsatellite marker at the SEMA3A promoter has been associated with chemosensitivity and radiosensitivity. Notably, our subsequent studies in primary t-AML demonstrate an expected up-regulation of SEMA3A that is EZH2-modulated. Furthermore, we have identified three biomodules that are co-expressed with SEMA3A and up-regulated in t-AML, one of which consists of previously characterized EZH2-repressed gene targets. The other two biomodules include MAPK8 and TATA box targets. Together, our studies suggest an important role for EZH2 targets in t-AML pathogenesis that warrants further study. These developed computational algorithms and systems biology strategies will enhance the knowledge discovery and hypothesis-driven analysis of multiple next generation sequencing data, for t-AML and other complex diseases.