Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia.
Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia.
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综合甲基化组和转录组分析揭示了小儿急性淋巴细胞白血病的新调节元件。
DOI：
10.1080/15592294.2015.1078050
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Taylor KH
中科院分区：
文献类型：
--
作者：
Almamun M;Levinson BT;van Swaay AC;Johnson NT;McKay SD;Arthur GL;Davis JW;Taylor KH
急性淋巴细胞白血病（ALL）是15岁以下儿童中最常见的癌症。除了遗传畸变，表观遗传修饰如DNA甲基化在癌症中发生改变并影响基因表达。为了鉴定ALL中的表观遗传学改变，使用甲基化CpG岛恢复测定法生成全基因组甲基化谱，然后进行下一代测序。在ALL患者中观察到超过25，000个差异甲基化区域（DMR），其中约90%存在于内含子或基因间区域。为了确定DMR的调控潜力，进行全转录组分析并与甲基化数据整合。异常启动子甲基化与转录调控、凋亡和增殖相关基因的表达改变有关。在内含子和基因间DMR内鉴定了新的增强子样序列。这些区域的异常甲基化与参与细胞周期过程、淋巴细胞活化和凋亡的邻近基因的表达改变有关。这些基因包括潜在的表观驱动基因，如SYNE 1、PTPRS、PAWR、HDAC 9、RGCC、MCOLN 2、林恩、TRAF 3、FLT 1和MELK，其可以为白血病细胞提供选择性优势。此外，还观察到表观遗传修饰基因、假基因和非编码RNA的差异表达，这加重了错误的表观遗传基因调控在ALL中的作用。
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with ∼90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighboring genes involved in cell cycle processes, lymphocyte activation and apoptosis. These genes include potential epi-driver genes, such as SYNE1, PTPRS, PAWR, HDAC9, RGCC, MCOLN2, LYN, TRAF3, FLT1, and MELK, which may provide a selective advantage to leukemic cells. In addition, the differential expression of epigenetic modifier genes, pseudogenes, and non-coding RNAs was also observed accentuating the role of erroneous epigenetic gene regulation in ALL.