Role of the Histone Methyltransferase MLL4 in Medulloblastoma

组蛋白甲基转移酶 MLL4 在髓母细胞瘤中的作用

• 批准号: 9380515
• 负责人: Min Gyu Lee
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380515
• 关键词: Brain; Cell Line; Cerebellum; ChIP-seq; Characteristics; Child; Childhood; Chromatin; DNA Methylation; DNA Modification Methylases; DNA Sequence; Data; Deposition; Development; Enhancers; Epigenetic Process; Event; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Heritability; Histone H3; Histones; Human; Incidence; Knock-out; Knockout Mice; Location; Lysine; MAPK14 gene; MLL2 gene; Malignant - descriptor; Mediating; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Modeling; Molecular; Molecular Profiling; Mus; Mutate; Mutation; Neuronal Differentiation; Neurons; Pathogenesis; Pathogenicity; Phenotype; Primary Brain Neoplasms; Ras Signaling Pathway; Regulator Genes; Reporting; Resolution; Role; SHH gene; Signal Pathway; Somatic Mutation; Stem cells; Suppressor-Effector T-Lymphocytes; TP53 gene; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Tretinoin; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumorigenicity; Western Blotting; anticancer research; base; design; driving force; epigenetic regulation; histone methylation; histone methyltransferase; histone modification; human stem cells; in vivo; innovation; insight; medulloblastoma; mouse model; mutant; nestin protein; novel; promoter; ras Guanine Nucleotide Exchange Factors; ras-GRF1; tumor; tumorigenic

PROJECT SUMMARY Medulloblastoma (MB) is the most common malignant primary brain tumor of children. MB development often results from the dysregulation of cellular signaling pathways, such as sonic hedgehog and wingless. Recently, epigenetic aberrations, which represent heritable aberrations in gene expression or cellular phenotypes without changes in DNA sequences, have emerged as a major driving force for tumorigenic events. Histone lysine methylation, a type of histone modification, is a hallmark of epigenetic and transcriptional regulation of gene expression and is modulated by histone methylation modifiers. In contrast to great advances in our understanding of cellular signaling pathways in MB genesis, the pathogenic role of altered histone methylation modifiers in MB development remains largely unknown. Of histone methylations, methylated histone H3 lysine 4 (H3K4) occupies most human gene promoters and is associated with active or poised genes. We previously showed that the H3K4 methyltransferase mixed-lineage leukemia 4 (MLL4; also called MLL2, ALR, and KMT2D) is indispensable for retinoic acid (RA)-induced neuronal differentiation of the model human stem cell line NT2/D1. Consistent with this, we also demonstrated that MLL4 activates the expression of several differentiation-specific genes by depositing methylated H3K4. Our additional results showed that Mll4 brain-specific knockout (BSKO) mice developed spontaneous MBs. These findings are consistent with recent massive sequencing studies of human MBs showing that the MLL4 gene often undergoes somatic mutations and deletions. Our long-term goal is to define the tumor-suppressive role of MLL4 in medulloblastoma pathogenesis. Our analysis of expression data suggests that Mll4-loss-induced MBs are close to the most malignant and metastatic MB subtype Group 3. Based on these definitive findings, our central hypothesis is that MLL4 acts as a tumor-suppressor against MB by activating the expression of tumor suppressor genes via regulation of epigenetic signatures. Here, we propose to study to 1) Assess the role of MLL4 in MB development using genetically engineered mouse models; 2) Determine the molecular mechanism underlying the genesis of Mll4-loss-driven MB; 3) Characterize the effect of Mll4 loss on epigenetic signatures during MB genesis. These studies will reveal the previously unknown epigenetic mechanism underlying MB pathogenesis and provide beneficial information for the development of MB therapies.

项目概要 髓母细胞瘤（MB）是儿童最常见的恶性原发性脑肿瘤。 MB经常发展 细胞信号通路失调的结果，例如音速刺猬和无翅。最近， 表观遗传畸变，代表基因表达或细胞表型的可遗传畸变，而无需 DNA 序列的变化已成为致瘤事件的主要驱动力。组蛋白赖氨酸 甲基化是一种组蛋白修饰，是基因表观遗传和转录调控的标志 表达并受到组蛋白甲基化修饰剂的调节。与我们理解上的巨大进步相反 MB 发生中细胞信号通路的影响，组蛋白甲基化修饰剂改变在 MB 中的致病作用 发展仍然很大程度上未知。在组蛋白甲基化中，甲基化组蛋白 H3 赖氨酸 4 (H3K4) 占据 大多数人类基因启动子，并与活跃或平衡的基因相关。我们之前展示过 H3K4 甲基转移酶混合谱系白血病 4（MLL4；也称为 MLL2、ALR 和 KMT2D）对于 视黄酸 (RA) 诱导模型人类干细胞系 NT2/D1 的神经元分化。符合 为此，我们还证明 MLL4 通过以下方式激活几种分化特异性基因的表达： 沉积甲基化的H3K4。我们的额外结果表明 Mll4 脑特异性敲除 (BSKO) 小鼠 产生自发的MB。这些发现与最近对人类进行的大规模测序研究一致 MBs 显示 MLL4 基因经常发生体细胞突变和缺失。我们的长期目标是 定义 MLL4 在髓母细胞瘤发病机制中的肿瘤抑制作用。我们对表达数据的分析 表明 Mll4 丢失诱导的 MB 接近最恶性和转移性的 MB 亚型第 3 组。 根据这些明确的发现，我们的中心假设是 MLL4 通过以下方式充当 MB 的肿瘤抑制剂： 通过表观遗传特征的调节激活肿瘤抑制基因的表达。在此，我们建议 研究目的 1) 使用基因工程小鼠模型评估 MLL4 在 MB 发育中的作用； 2） 确定 Mll4 丢失驱动的 MB 发生的分子机制； 3）表征效果 MB 发生过程中表观遗传特征 Mll4 丢失。这些研究将揭示以前未知的 MB发病机制的表观遗传机制，为MB的发展提供有益的信息 MB疗法。