Identification of a differentiation stall in epithelial mesenchymal transition in histone H3-mutant diffuse midline glioma.
Identification of a differentiation stall in epithelial mesenchymal transition in histone H3-mutant diffuse midline glioma.
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DOI：
10.1093/gigascience/giaa136
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发表时间：
2020-12-15
期刊：
影响因子：
9.2
通讯作者：
Vaske OM
中科院分区：
文献类型：
--
作者：
Sanders LM;Cheney A;Seninge L;van den Bout A;Chen M;Beale HC;Kephart ET;Pfeil J;Learned K;Lyle AG;Bjork I;Haussler D;Salama SR;Vaske OM
具有组蛋白H3K27M(H3K27M)突变的弥漫性中线胶质瘤发生在儿童早期，以侵袭性表型和H3K27me3的全局性减少为特征，H3K27me3是一种调节分化和发育的表观遗传标记。H3K27M突变的时间和对早期胚胎脑发育的影响尚未完全确定。我们分析了多个公开可用的RNA测序数据集，以确定H3K27M和非K27M儿童胶质瘤之间的差异表达基因。我们发现，在差异表达的基因中，参与上皮-间充质转化(EMT)的基因明显过度表达。总体而言，与非K27M肿瘤相比，H3K27M肿瘤中EMT前基因的表达增加，而EMT后基因的表达降低。我们假设H3K27M可能通过延缓早期大脑发育所需的EMT而促进胶质瘤的发生，并使用另一个公开可用的数据集来评估这一假设，该数据集来自发育中的脑器官的单细胞和批量RNA测序数据。这一分析揭示了H3K27M肿瘤与EMT前正常脑细胞之间的相似之处。最后，之前发表的H3K27M和非K27M胶质瘤的单细胞RNA测序数据集显示了EMT不同阶段的细胞亚群。特别是，与H3.3K27M肿瘤相比，H3.1K27M肿瘤类似于较晚的EMT阶段。我们的数据分析表明，这种突变可能与分化停滞有关，这明显是由于未能通过类似EMT的发育过程，并且H3K27M细胞优先存在于EMT前细胞表型。这项研究展示了如何通过对以前发表的几个数据集的联合分析来得出新的生物学见解，强调了及时向社区提供基因组数据的重要性。
Diffuse midline gliomas with histone H3 K27M (H3K27M) mutations occur in early childhood and are marked by an invasive phenotype and global decrease in H3K27me3, an epigenetic mark that regulates differentiation and development. H3K27M mutation timing and effect on early embryonic brain development are not fully characterized. We analyzed multiple publicly available RNA sequencing datasets to identify differentially expressed genes between H3K27M and non-K27M pediatric gliomas. We found that genes involved in the epithelial-mesenchymal transition (EMT) were significantly overrepresented among differentially expressed genes. Overall, the expression of pre-EMT genes was increased in the H3K27M tumors as compared to non-K27M tumors, while the expression of post-EMT genes was decreased. We hypothesized that H3K27M may contribute to gliomagenesis by stalling an EMT required for early brain development, and evaluated this hypothesis by using another publicly available dataset of single-cell and bulk RNA sequencing data from developing cerebral organoids. This analysis revealed similarities between H3K27M tumors and pre-EMT normal brain cells. Finally, a previously published single-cell RNA sequencing dataset of H3K27M and non-K27M gliomas revealed subgroups of cells at different stages of EMT. In particular, H3.1K27M tumors resemble a later EMT stage compared to H3.3K27M tumors. Our data analyses indicate that this mutation may be associated with a differentiation stall evident from the failure to proceed through the EMT-like developmental processes, and that H3K27M cells preferentially exist in a pre-EMT cell phenotype. This study demonstrates how novel biological insights could be derived from combined analysis of several previously published datasets, highlighting the importance of making genomic data available to the community in a timely manner.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
5.3
作者：
Carver, EA;Jiang, RL;Gridley, T
通讯作者：
Gridley, T
影响因子：
9.7
作者：
Howng, SL;Wu, CH;Hong, YR
通讯作者：
Hong, YR
影响因子：
4
作者：
Bolós, V;Peinado, H;Cano, A
通讯作者：
Cano, A
影响因子：
5.9
作者：
Field, Andrew R.;Jacobs, Frank M. J.;Haussler, David
通讯作者：
Haussler, David