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纳米孔测序实现全面转座子表观基因组分析。

Nanopore Sequencing Enables Comprehensive Transposable Element Epigenomic Profiling.

机构信息

Mater Research Institute, University of Queensland, Woolloongabba, QLD 4102, Australia.

Mater Research Institute, University of Queensland, Woolloongabba, QLD 4102, Australia.

出版信息

Mol Cell. 2020 Dec 3;80(5):915-928.e5. doi: 10.1016/j.molcel.2020.10.024. Epub 2020 Nov 12.

Abstract

Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization.

摘要

转座元件 (TEs) 驱动基因组进化,是发病机制的重要来源,包括癌症。虽然 CpG 甲基化调控 TE 活性,但迄今为止,移动的人类 TE 的局部位点甲基化景观在很大程度上仍难以获得。在这里,我们应用新的计算工具和长读长纳米孔测序技术,直接推断海马体、心脏和肝脏以及配对的肿瘤和非肿瘤肝脏中新的和现存的 TE 插入的 CpG 甲基化。与无差别随机过程相反,我们发现癌症中年轻的长散布元件 1 (LINE-1) 逆转录转座子明显去甲基化,通常与相邻基因组和其他 TE 不同。SINE-VNTR-Alu (SVA) 逆转录转座子,包括其内部串联重复相关的 CpG 岛,几乎普遍甲基化。我们在正常组织中遇到异常表达的年轻 LINE-1 的等位基因特异性 TE 甲基化和去甲基化。最后,我们恢复了肿瘤特异性 LINE-1 插入及其逆转座标志的完整序列,证明了长读测序如何能够同时调查表观基因组并检测体细胞 TE 动员。

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