TY - JOUR AU - Al-Ali, Ruslan AU - Bauer, Katharina AU - Park, Jong-Whi AU - Al Abdulla, Ruba AU - Fermi, Valentina AU - von Deimling, Andreas AU - Herold-Mende, Christel AU - Mallm, Jan-Philipp AU - Herrmann, Carl AU - Wick, Wolfgang AU - Turcan, Şevin PY - 2019 DA - 2019/12/05 TI - Single-nucleus chromatin accessibility reveals intratumoral epigenetic heterogeneity in IDH1 mutant gliomas JO - Acta Neuropathologica Communications SP - 201 VL - 7 IS - 1 AB - 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. SN - 2051-5960 UR - https://doi.org/10.1186/s40478-019-0851-y DO - 10.1186/s40478-019-0851-y ID - Al-Ali2019 ER -