1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2].
1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2].
Nature. 2014 Jun 26;510(7506):537-41. doi: 10.1038/nature13268. Epub 2014 May 18.
Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. 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), 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.
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。髓母细胞瘤，一种具有临床挑战性的恶性儿童脑肿瘤，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 通路激活、SHH 通路激活以及特征不太明显的第 3 组和第 4 组）中都发现了反复出现的变化，但许多病例仍然缺乏明显的遗传驱动因素。在这里，我们展示了来自 34 个人类和 5 个鼠类肿瘤以及 8 个人类和 3 个鼠类正常对照的全基因组亚硫酸氢盐测序数据，同时还增加了匹配的全基因组、RNA 和染色质免疫沉淀测序数据。这个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相互作用的几个特征，及其对髓母细胞瘤病理生理学的影响。最值得注意的是，与基因表达增加相关的高度普遍的低甲基化区域，延伸到转录起始位点下游数十千碱基。与转录因子结合位点相关的低甲基化焦点揭示了亚组之间不同的转录网络，而由于 DNA 甲基化谷中被抑制的染色质重新正常化导致的甲基化增加与基因表达呈正相关。影响多达三分之一基因组的大的、部分甲基化的域表现出亚组特异性的突变率增加和基因沉默。表观遗传改变还影响了新的髓母细胞瘤候选基因（例如，LIN28B），导致启动子使用的替代和/或信使 RNA/微 RNA 表达的差异。对鼠类髓母细胞瘤和前体细胞甲基化的分析表明，许多改变具有体细胞起源。我们的数据为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提供了深入了解，这些改变在更广泛的发育和疾病背景下可能也很重要。
