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5-羟甲基胞嘧啶优先靶向 IDH1 突变型高级别胶质瘤中上调的基因。

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.

机构信息

MacFeeters-Hamilton Centre for Neuro-Oncology Research, University Health Network, Toronto, Canada.

Division of Respiratory Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan.

出版信息

Acta Neuropathol. 2018 Apr;135(4):617-634. doi: 10.1007/s00401-018-1821-3. Epub 2018 Feb 10.

DOI:10.1007/s00401-018-1821-3
PMID:29428975
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5978937/
Abstract

Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.

摘要

神经胶质瘤表现出表观遗传失调，表现在 IDH1 突变肿瘤中出现的神经胶质瘤 CpG 岛甲基化表型（G-CIMP）。5-羟甲基胞嘧啶（5hmC）参与神经胶质瘤的发病机制；然而，其在 IDH1 突变神经胶质瘤中的作用尚未完全阐明。为了进一步研究 IDH1 突变神经胶质瘤中的 5hmC，我们使用定量的基因座特异性方法，研究了 IDH1 突变和野生型高级别神经胶质瘤（HGG）中的 5hmC。表现出高 5hmC 丰度和差异羟甲基化区域（DHMR）的区域富集了与神经胶质瘤发病机制相关的增强子。在这些区域中，IDH1 突变肿瘤比野生型具有更高的 5hmC。5hmC 有助于 G-CIMP 基因的整体甲基化状态。5hmC 靶向基因体区域与基因表达增加显著相关。特别是，在 IDH1 突变队列中高表达的基因中，5hmC 增加与基因表达增加之间存在很强的相关性。总的来说，基因座特异性获得 5hmC 靶向调控区域与过表达基因相关，提示 5hmC 在 IDH1 突变型 HGG 中具有重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/96a49ec8b887/401_2018_1821_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/4df4c214bd38/401_2018_1821_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/9937cd6d6bb3/401_2018_1821_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/1b304397f333/401_2018_1821_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/173bc705d662/401_2018_1821_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/96a49ec8b887/401_2018_1821_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/4df4c214bd38/401_2018_1821_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/9937cd6d6bb3/401_2018_1821_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/1b304397f333/401_2018_1821_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/173bc705d662/401_2018_1821_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a338/5978937/96a49ec8b887/401_2018_1821_Fig5_HTML.jpg

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