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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

MGMT 表观遗传学：基因体甲基化的影响和从各种癌症类型的综合甲基化、转录组学和染色质分析得出的其他见解

卷 21, 期 4, 2021

发表于: 02 February, 2021

页: [360 - 374] 页: 15

弟呕挨: 10.2174/1568009621666210203111620

价格: $65

摘要

背景：MGMT（O6-甲基鸟嘌呤-DNA 甲基转移酶）主要负责限制一些广泛使用的化疗药物的活性，包括替莫唑胺 (TMZ) 和卡莫司汀 (BCNU)。编码该蛋白的基因受表观遗传调控，其启动子区域的甲基化评估用于预测神经胶质瘤患者对 TMZ 的反应。 方法：在本报告中，我们采用生物信息学方法来阐明 MGMT 的表观遗传调控。用于分析的集成了 > 8,600 个人类组织（代表 31 种不同的癌症类型）和 500 个人类癌细胞系样本的全基因组甲基化和转录数据集。对结果解释也至关重要的是来自 ENCODE 项目的公开数据：组蛋白修饰轨迹（通过 ChIP-seq）和 DNase I 超敏反应（通过 DNaseseq），以及代表性细胞系（HeLa-S3）的甲基化和转录数据, HMEC, K562)。 结果和讨论：我们能够验证（或许更全面）CpG 甲基化在启动子区域和基因体对 MGMT 转录的对比影响。虽然 MGMT 启动子由甲基化水平显示与 MGMT mRNA 计数呈高度负相关 (R) 的 CpG 位点填充，但基因体包含表现出高正 R 值的 CpG 位点。在癌症类型中具有非常高负 R 的启动子 CpG 位点包括 cg12981137、cg12434587 和 cg00618725。值得注意的基因体 CpG 位点（跨癌症类型的高阳性 R）包括 cg00198994（内含子 1）、cg04473030（内含子 2）和 cg07367735（内含子 4）。对于某些癌症类型，例如黑色素瘤，基因体甲基化似乎是 MGMT 转录的更好预测因子（与启动子甲基化相比）。通常，相对于组织，细胞系中 CpG 甲基化与 MGMT 表达的 R 值更高。此外，这些相关性在某些癌症类型中明显更为突出，例如结直肠癌、肾上腺皮质癌、食道癌、皮肤癌、头颈癌以及胶质母细胞瘤。正如预期的那样，启动子区域的低甲基化与更开放的染色质相关，组蛋白的富集标志着 H3K4m1、H3K4m2、H3K4m3 和 H3K9ac。 结论：总的来说，我们的分析说明了启动子和基因体甲基化对 MGMT 表达的对比影响。这些观察结果可能有助于改进 MGMT 的诊断分析。

关键词: MGMT、表观遗传学、甲基化、TCGA、编码、癌症。

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