The presence of genome-wide DNA hypermethylation is a hallmark of lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) mutations. Further molecular classification of IDH mutant gliomas is defined by the presence (IDHmut-codel) or absence (IDHmut-noncodel) of hemizygous codeletion of chromosome arms 1p and 19q. Despite the DNA hypermethylation seen in bulk tumors, intra-tumoral heterogeneity at the epigenetic level has not been thoroughly analyzed. To address this question, we performed the first epigenetic profiling of single cells in a cohort of 5 gliomas with IDH1 mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq). Using the Fluidigm HT IFC microfluidics platform, we generated chromatin accessibility maps from 336 individual nuclei, and identified variable promoter accessibility of non-coding RNAs in LGGs. Interestingly, local chromatin structures of several non-coding RNAs are significant factors that contribute to heterogeneity, and show increased promoter accessibility in IDHmut-noncodel samples. As an example for clinical significance of this result, we identify CYTOR as a poor prognosis factor in gliomas with IDH mutation. Open chromatin assay points to differential accessibility of non-coding RNAs as an important source of epigenetic heterogeneity within individual tumors and between molecular subgroups. Rare populations of nuclei that resemble either IDH mutant molecular group co-exist within IDHmut-noncodel and IDHmut-codel groups, and along with non-coding RNAs may be an important issue to consider for future studies, as they may help guide predict treatment response and relapse.A web-based explorer for the data is available at shiny.turcanlab.org.

中文翻译：

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单核染色质可及性揭示IDH1突变神经胶质瘤的瘤内表观遗传异质性。

全基因组DNA超甲基化的存在是具有异柠檬酸脱氢酶（IDH）突变的低级神经胶质瘤（LGG）的标志。IDH突变神经胶质瘤的进一步分子分类由染色体臂1p和19q的半合子编码缺失的存在（IDHmut-codel）或不存在（IDHmut-noncodel）定义。尽管在大块肿瘤中发现了DNA甲基化过高，但尚未对表观遗传水平上的肿瘤内异质性进行全面分析。为了解决这个问题，我们使用高通量测序（snATAC-seq）对转座酶可及染色质进行了单核测定，对5个IDH1突变的神经胶质瘤进行了单细胞表观遗传学分析。使用Fluidigm HT IFC微流体平台，我们从336个单个核生成了染色质可及性图，并确定了LGG中非编码RNA的可变启动子可及性。有趣的是，几个非编码RNA的局部染色质结构是导致异质性的重要因素，并且在IDHmut-noncodel样品中显示出增加的启动子可及性。作为该结果临床意义的一个例子，我们确定CYTOR是IDH突变的神经胶质瘤的不良预后因素。开放式染色质测定法指出非编码RNA的差异可及性是单个肿瘤内以及分子亚组之间表观遗传异质性的重要来源。与IDHmut-noncodel和IDHmut-codel组共存的，与IDH突变分子基团相似的稀有细胞核，以及与非编码RNA一起可能是未来研究中需要考虑的重要问题，