Hovestadt V, Jones D T, Picelli S, et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 2014,510(7506): 537-541.

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.

表观遗传学的改变，DNA甲基化和核染色质结构的破坏，目前被认为是肿瘤发生过程中最普遍的的特征。这种现象也毫无例外的发生在儿童脑的髓母细胞瘤中。尽管从目前基因组学的研究中，对髓母细胞瘤取得了较大的进展，然而四种不同分子亚型（WNT、SHH、Group 3及Group 3）间均存在许多不同的特点，许多案例仍缺乏明显的基因启动子。作者对34个人类和5个鼠类动物的髓母细胞瘤，加上8个人类和3个鼠类正常对照组做了深入的研究，包括对整个基因组测序、RNA和染色质免疫共沉淀测序。这些综合性的数据，能够帮助我们从基因组学、表观基因组学和转录基因组学方面解释一些不同亚型间存在不同的特征，以及对髓母细胞瘤病理生理学方面的影响。低甲基化与基因表达的增加密切相关，导致转录起始位点下游数千个碱基对的扩增，不同亚型髓母细胞瘤不同的转录信号通路与转录因子结合位点区域的局部低甲基化有关，而甲基化的增加导致DNA甲基化过程中被抑制的核染色质正常化。甲基化影响大约三分之一的基因组学，导致其基因突变率增加，仅极少部分表现为基因沉默。表观遗传学的改变同样影响异常的髓母细胞瘤候选基因（例如LIN28B）的变化，从而导致启动子和/或信使RNA及microRNA表达的不同。通过对鼠类髓母细胞瘤和前体细胞甲基化的分析，表明许多改变都起源于前体细胞。这些数据能够使我们更好的了解转录和基因组的表观遗传调控髓母细胞瘤的发病机制。