Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing
Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing
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DOI：
10.1038/nature13268
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发表时间：
2014-06-26
期刊：
影响因子：
64.8
通讯作者：
Lichter, Peter
中科院分区：
文献类型：
--
作者：
Hovestadt, Volker;Jones, David T. W.;Lichter, Peter
表观遗传改变，即DNA甲基化和染色质结构的破坏，现在被认为是肿瘤发生的普遍特征（1）。髓母细胞瘤是一种临床上具有挑战性的儿童恶性脑肿瘤，也不例外。尽管最近的基因组学研究取得了很大进展，在四个不同的肿瘤亚组（WNT-途径激活的，SHH-途径激活的，以及特征不太好的第3组和第4组）中的每一个中都发现了复发性变化（2-4），但许多病例仍然缺乏明显的遗传驱动因素。在这里，我们提出了全基因组亚硫酸氢盐测序数据，从34人和5个小鼠肿瘤加上8人和3个小鼠正常对照，增强匹配的全基因组，RNA和染色质免疫沉淀测序数据。这一全面的数据集使我们能够破译基因组，表观基因组和转录组之间的相互作用及其对髓母细胞瘤病理生理学的影响的几个特征。最值得注意的是与增加的基因表达相关的高度普遍的低甲基化区域，在转录起始位点的下游延伸数十个脱氢酶。与转录因子结合位点相关的低甲基化焦点区域揭示了亚组之间的差异转录网络，而由于DNA甲基化谷中被抑制的染色质重新正常化而导致的甲基化增加与基因表达呈正相关。大的，部分甲基化的结构域影响到三分之一的基因组显示出增加的突变率和基因沉默的亚组特异性的方式。表观遗传学改变也影响了新的髓母细胞瘤候选基因（例如LIN 28 B），导致替代启动子使用和/或差异信使RNA/microRNA表达。对小鼠髓母细胞瘤和髓母细胞甲基化的分析表明，许多改变是体细胞起源的。我们的数据提供了深入了解髓母细胞瘤发病机制中转录和基因组组织的表观遗传调控，这可能在更广泛的发育和疾病背景下也很重要。
Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis(1). Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups(WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4)(2-4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.