Anastasia E. Hains, Kashish Chetal, Tsunetoshi Nakatani, Joana G. Marques, Andreas Ettinger, Carlos A. O. Biagi Junior, Adriana Gonzalez-Sandoval, Renjitha Pillai, Mariella G. Filbin, Maria-Elena Torres-Padilla, Ruslan I. Sadreyev, Capucine Van Rechem
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引用次数: 0
摘要
致命的弥漫性中线胶质瘤(DMG)的特点是H3.1或H3.3中存在不可治愈的H3K27M突变。K27M 会阻碍分化,从而损害正常发育。对可靶向通路的鉴定仍处于探索阶段。为了实现这一目标,我们采用多组学方法评估了来自H3.1K27M和H3.3K27M亚群的DMG细胞中的复制时序图、转录组学和细胞周期特征,并与健康脑组织进行了比较性综合数据分析。DMG 细胞在每个亚组中的复制时间不同,这反过来又与基因表达的显著差异相关。在 S 期表达不同的基因参与了与 DNA 复制有关的各种途径。与正常脑细胞相比,我们发现在DMG细胞系的细胞周期早期,DNA复制基因的表达量有所增加。此外,与正常脑细胞相比,DMG 细胞中复制起源之间的距离更小,分叉速度更慢,这是复制压力的一种表现。与这些发现一致的是,与正常脑细胞相比,DMG 肿瘤呈现出较高的复制压力特征。最后,DMG 细胞对复制压力疗法特别敏感。这种全基因组多组学方法深入揭示了通过H3K27M突变调节DMG细胞周期的过程,并确定了DNA复制的药理学脆弱性,为这种无法治愈的疾病找到了一种潜在的新型治疗策略。
Multi-omics approaches reveal that diffuse midline gliomas present altered DNA replication and are susceptible to replication stress therapy
The fatal diffuse midline gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling differentiation. The identification of targetable pathways remains very poorly explored. Toward this goal, we undertake a multi-omics approach to evaluate replication timing profiles, transcriptomics, and cell cycle features in DMG cells from both H3.1K27M and H3.3K27M subgroups and perform a comparative, integrative data analysis with healthy brain tissue. DMG cells present differential replication timing in each subgroup, which, in turn, correlates with significant differential gene expression. Differentially expressed genes in S phase are involved in various pathways related to DNA replication. We detect increased expression of DNA replication genes earlier in the cell cycle in DMG cell lines compared to normal brain cells. Furthermore, the distance between origins of replication in DMG cells is smaller than in normal brain cells and their fork speed is slower, a read-out of replication stress. Consistent with these findings, DMG tumors present high replication stress signatures in comparison to normal brain cells. Finally, DMG cells are specifically sensitive to replication stress therapy. This whole genome multi-omics approach provides insights into the cell cycle regulation of DMG via the H3K27M mutations and establishes a pharmacologic vulnerability in DNA replication, which resolves a potentially novel therapeutic strategy for this non-curable disease.
Genome BiologyBiochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍:
Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens.
With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category.
Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.