Abstract
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.
Highlights
Isocitrate dehydrogenase 1 (IDH1), and to a lesser extent, its mitochondrial homolog, IDH2, are mutated in a majority of adult lower grade gliomas (LGGs) [46]
Our cohort was primarily composed of WHO grade II gliomas, with the exception of one WHO grade III IDHmut-noncodel glioma, and all tumors harbored an IDH1 R132 mutation (Table 1)
Our results indicate that CYTOR could be of importance in the pathogenesis of isocitrate dehydrogenase (IDH) mutant tumors, as high CYTOR expression is associated with poor overall survival
Summary
Isocitrate dehydrogenase 1 (IDH1), and to a lesser extent, its mitochondrial homolog, IDH2, are mutated in a majority of adult lower grade gliomas (LGGs) [46]. The most common IDH1 mutation in gliomas (IDH1 R132) occurs in the catalytic domain of IDH1 and confers the ability to produce 2hydroxyglutarate (2-HG) [7]. 2-HG competitively inhibits enzymes that use αKG as a cofactor, such as TET family of enzymes and Jmj-C domain containing histone demethylases, leading to DNA hypermethylation, Al-Ali et al Acta Neuropathologica Communications (2019) 7:201 sequencing (snATAC-seq) on a subset of 5 patient samples. We identified heterogeneity in promoter accessibility within and between IDHmutcodel and IDHmut-noncodel samples. Our results indicate differential accessibility of non-coding RNAs such as the CYTOR locus that exhibits a profound increase in promoter accessibility within IDHmutnoncodel tumors. We identify CYTOR as a poor prognosis factor in gliomas with IDH mutation. Our results point to differential accessibility of non-coding RNAs as an important source of epigenetic heterogeneity within individual tumors and between molecular subgroups. The molecules identified are promising targets for future molecular research
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