The epigenetic mechanisms of high-grade pediatric glioblastoma

小儿高级别胶质母细胞瘤的表观遗传机制

基本信息

  • 批准号:
    9309372
  • 负责人:
  • 金额:
    $ 38.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-06-15 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

Diffuse intrinsic pontine glioma (DIPG) is an aggressive primary brain tumor found exclusively in children. The median survival for DIPG patients is about one year from diagnosis, with no treatment in sight. Recent studies have uncovered driver mutations for DIPG, specifically, somatic mutations in the H3F3A gene have been observed in majority of DIPG cases. H3F3A encodes histone H3 variant H3.3 that plays an important role in regulating gene expression during development. The predominant mutation at H3F3A leads to amino acid change at lysine (K) 27 residue of H3.3 to methionine (M) (H3K27M). In human cells, there are two genes that encode H3.3, which is assembled into nucleosomes in a replication-independent nucleosome assembly pathway. In addition, there are 13 genes encoding canonical histones H3.1 and H3.2, which differ from H3.3 by 4 or five amino acids and are assembled into nucleosomes in a replication-coupled process. Lysine 27 is conserved among all these histone H3 proteins. Therefore, it is unknown how H3.3 K27M mutation, which occurs at one allele of H3F3A gene, promotes tumorigenesis. H3K27 is modified post-translationally by either acetylation or methylation. H3K27 methylation is catalyzed by the PRC2 lysine methyltransferase and plays an important role in gene silencing during stem cell differentiation and maintenance. We and others have shown that a global loss of H3K27 methylation occurs in DIPG cells containing K27M mutation, which is due to inhibition of PRC2 enzymatic activity by H3.3M27 mutant proteins. In addition to the global loss of H3K27me3 that is associated with gene activation, we also observed that H3K27me3 is present at the gene promoters of about 800 genes. These genes are largely silenced and are enriched in pathways associated with tumorigenesis. In addition, we performed an shRNA screen to identify genes that when depleted inhibit the proliferation of DIPG cells. We found that Wnt5a, a protein involved in non-canonical Wnt signaling pathway, inhibits proliferation of DIPG cells. Based on these exciting results, we hypothesize that H3.3M27 mutation proteins reprogram epigenetic states and gene expression of a key regulator(s)/pathway(s) and thereby promotes tumorigenesis. In this proposal, we will elucidate the molecular mechanism whereby the 800 genes with H3K27me3 and determine to what extent “gain” of H3K27me3 at these genes promotes tumorigenesis. In addition, we will elucidate the molecular mechanisms whereby Wnt5a and several components of Wnt5a signaling pathway are required for the proliferation of DIPG cells and test the hypothesis that inhibition of components of Wnt5a signaling pathway is a viable approach for the future treatment of DIPG. Together, the proposed studies will not only discover the molecular basis of tumorigenesis of DIPG, but also lay the foundation for molecularly targeted therapies for this deadly disease.
弥漫性桥脑胶质瘤(DIPG)是一种侵袭性的原发脑瘤,仅见于儿童。这个 DIPG患者的中位生存期距离确诊约一年,目前还看不到治疗的迹象。最新研究 已经发现了DIPG的驱动因素突变,具体地说,H3F3A基因的体细胞突变 在大多数DIPG病例中观察到。H3F3A编码组蛋白H3变异体H3.3,该变异体在 调控发育过程中的基因表达。H3F3A的主要突变导致氨基酸 将H3.3的赖氨酸(K)27位变为蛋氨酸(M)(H3K27M)。在人类细胞中,有两个基因 编码H3.3,H3.3在复制无关的核小体组装中组装成核小体 路径。此外,还有13个基因编码典型的组蛋白H3.1和H3.2,它们与H3.3的差异在于 4或5个氨基酸,并在复制偶联过程中组装成核小体。赖氨酸27是 在所有这些组蛋白H3蛋白中保守。因此,目前尚不清楚H3.3 K27M是如何发生突变的 发生在H3F3A基因的一个等位基因上,促进肿瘤的发生。 H3K27通过乙酰化或甲基化在翻译后修饰。H3K27甲基化的催化作用是 PRC2赖氨酸甲基转移酶在干细胞分化过程中的基因沉默中起重要作用 和维护。我们和其他人已经证明,在DIPG细胞中发生了H3K27甲基化的全球丢失 含有K27M突变,这是由于H3.3M27突变蛋白抑制了PRC2的酶活性所致。 除了与基因激活有关的H3K27me3的全球丢失外,我们还观察到 H3K27me3存在于约800个基因的启动子上。这些基因在很大程度上是沉默的, 富含与肿瘤发生相关的途径。此外,我们还进行了shRNA筛选以确定 当耗尽时,抑制DIPG细胞增殖的基因。我们发现Wnt5a,一种参与 非规范的Wnt信号通路,抑制DIPG细胞的增殖。基于这些令人振奋的结果,我们 假设H3.3M27突变蛋白重新编程关键基因的表观遗传状态和基因表达 调节因子(S)/途径(S),从而促进肿瘤的发生。在这个提案中,我们将阐明分子 800个基因与H3K27me3结合的机制,并确定H3K27me3在 这些基因促进了肿瘤的发生。此外,我们还将阐明Wnt5a的分子机制 而Wnt5a信号通路的几个组成部分是DIPG细胞增殖和检测所必需的 假设抑制Wnt5a信号通路的组件是未来可行的方法 DIPG的治疗。总之,拟议中的研究不仅将发现肿瘤发生的分子基础 DIPG,但也为这种致命疾病的分子靶向治疗奠定了基础。

项目成果

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Zhiguo Zhang其他文献

Zhiguo Zhang的其他文献

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{{ truncateString('Zhiguo Zhang', 18)}}的其他基金

Epigenetic dependence of diffuse midline glioma with H3K27M mutation
具有 H3K27M 突变的弥漫性中线胶质瘤的表观遗传依赖性
  • 批准号:
    10736036
  • 财政年份:
    2023
  • 资助金额:
    $ 38.03万
  • 项目类别:
Roles of Chromatin Remodeler CHD2 in Diffuse Midline Glioma with Onco-Histone Mutations
染色质重塑蛋白 CHD2 在具有癌组蛋白突变的弥漫性中线胶质瘤中的作用
  • 批准号:
    10667276
  • 财政年份:
    2023
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanism of Epigenetic Inheritance
表观遗传机制
  • 批准号:
    10641444
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanism of Epigenetic Inheritance
表观遗传机制
  • 批准号:
    10447571
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanism of Epigenetic Inheritance
表观遗传机制
  • 批准号:
    10669104
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanism of Epigenetic Inheritance
表观遗传机制
  • 批准号:
    10796601
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanisms of Epigenetic inheritance
表观遗传机制
  • 批准号:
    9751887
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Mechanisms of Epigenetic inheritance
表观遗传机制
  • 批准号:
    9067600
  • 财政年份:
    2016
  • 资助金额:
    $ 38.03万
  • 项目类别:
Identify and characterize genes involved in X-chromosome inactivation
鉴定和表征参与 X 染色体失活的基因
  • 批准号:
    8216410
  • 财政年份:
    2012
  • 资助金额:
    $ 38.03万
  • 项目类别:
The role of a histone H4 phosphorylation in drug resistance
组蛋白 H4 磷酸化在耐药性中的作用
  • 批准号:
    8292471
  • 财政年份:
    2012
  • 资助金额:
    $ 38.03万
  • 项目类别:

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