Functional role of genes and pathways in histone H3 mutated gliomas

组蛋白 H3 突变神经胶质瘤中基因和通路的功能作用

• 批准号: 417182005
• 负责人: Professor Dr. Martin Hasselblatt
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417182005?language=en
• 关键词: Functional; role; genes; pathways; histone

Histones are evolutionarily highly conserved and their epigenetic modification plays a key role in the differentiation of eukaryotic cells and brain development. In brain tumors, histone H3 mutations (K27M, G34R and G34V) have been described as driver mutations in a subgroup of malignant gliomas showing aggressive biological behavior and poor response to therapy. Histone H3 mutations have been shown to cause transcriptional dysregulation, but little is known on functionally relevant genes and signaling pathways. Within the proposed DFG project, we aim at identifying genes and pathways involved in the biology of histone H3-mutated gliomas, which are of functional and clinical relevance. In particular, we want to better understand (1) how overexpression of mutated histone H3 affects central nervous system development, (2) investigate which genes and signaling pathways are involved in the detrimental effects of histone H3 mutations and (3) examine the functional role and clinical relevance of these genes and signaling pathways in histone H3 mutated tumors. To this end, we have established a fly model to study the effect of ubiquitous and cell-type specific over-expression of human mutated histone H3.3. In this model, we will employ a dual approach. In an unbiased approach we will (1) perform Gal4-UAS modifier screens by crossing in 1099 different fly strains expressing siRNA constructs of genes expressed in the fly nervous system and study the effect of ubiquitous and cell-type specific knockdown on the phenotype caused by overexpression of mutated histone H3.3. In parallel, we will (2) study the functional role of genes found to be over-expressed functional role of fly orthologues of human genes over-expressed in K27M mutated gliomas in this model. Results will be further validated by studying the effect of pharmacological inhibition of identified pathways. Expression, functional role (histone trimethylation, proliferation, migration) and clinical relevance of identified genes and signaling pathways will be examined in human histone H3-mutated tumor cell lines as well as clinically well-annotated histone H3-mutated tumor specimens, respectively. The results of this project will contribute to a better understanding of genes and pathways involved in the biology of histone H3-mutated gliomas. In the long term, they are expected to aid better treatments of patients harboring histone H3-mutated gliomas.

组蛋白在进化上高度保守，其表观遗传修饰在真核细胞的分化和大脑发育中发挥着关键作用。在脑肿瘤中，组蛋白H3突变（K27 M、G34 R和G34 V）已被描述为恶性胶质瘤亚组中的驱动突变，其显示侵袭性生物学行为和对治疗的不良反应。组蛋白H3突变已被证明会导致转录失调，但对功能相关的基因和信号通路知之甚少。在拟议的DFG项目中，我们的目标是确定参与组蛋白H3突变神经胶质瘤生物学的基因和途径，这些基因和途径具有功能和临床相关性。特别是，我们希望更好地了解（1）突变组蛋白H3的过度表达如何影响中枢神经系统发育，（2）研究哪些基因和信号通路参与了组蛋白H3突变的有害影响，（3）检查这些基因和信号通路在组蛋白H3突变肿瘤中的功能作用和临床相关性。为此，我们建立了一个苍蝇模型来研究普遍存在的和细胞类型特异性过表达的人突变组蛋白H3.3的影响。在这个模型中，我们将采用双重方法。在无偏的方法中，我们将（1）通过在1099种表达果蝇神经系统中表达的基因的siRNA构建体的不同果蝇品系中杂交来进行Gal 4-UAS修饰剂筛选，并研究普遍存在的和细胞类型特异性敲低对由突变组蛋白H3.3的过表达引起的表型的影响。与此同时，我们将（2）研究在该模型中被发现过表达的基因的功能作用-在K27 M突变的神经胶质瘤中过表达的人类基因的果蝇直系同源物的功能作用。将通过研究已识别途径的药理学抑制作用进一步验证结果。将分别在人组蛋白H3突变的肿瘤细胞系以及临床上注释良好的组蛋白H3突变的肿瘤标本中检查已鉴定基因和信号传导途径的表达、功能作用（组蛋白三甲基化、增殖、迁移）和临床相关性。该项目的结果将有助于更好地了解组蛋白H3突变胶质瘤生物学中涉及的基因和途径。从长远来看，它们有望帮助更好地治疗携带组蛋白H3突变的胶质瘤患者。