Role of the Histone Methyltransferase MLL4 in Medulloblastoma

项目摘要 髓母细胞瘤（MB）是儿童最常见的恶性原发性脑肿瘤。甲基溴的发展往往 结果从失调的细胞信号通路，如音刺猬和无翅。最近， 表观遗传畸变，代表基因表达或细胞表型中的可遗传畸变， DNA序列的改变已经成为肿瘤发生事件的主要驱动力。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，并由组蛋白甲基化修饰剂调节。与我们在理解上的巨大进步相比 MB发生中的细胞信号传导途径，改变的组蛋白甲基化修饰剂在MB中的致病作用， 发展情况仍然很不清楚。在组蛋白甲基化中，甲基化的组蛋白H3赖氨酸4（H3 K4）占据 大多数人类基因启动子，并与活跃或稳定的基因相关。我们之前已经证明了H3 K4 甲基转移酶混合谱系白血病4（MLL 4;也称为MLL 2，ALR和KMT 2D）是不可或缺的， 维甲酸（RA）诱导的模型人干细胞系NT 2/D1的神经元分化。符合 因此，我们还证明了MLL 4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H3 K4。我们的额外结果显示M114脑特异性敲除（BSKO）小鼠 出现了自发性心肌梗塞这些发现与最近的人类基因组大规模测序研究一致。 MB显示MLL 4基因经常经历体细胞突变和缺失。我们的长期目标是 明确MLL 4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 提示M114缺失诱导的MB接近最恶性和转移性MB亚型组3。基于 基于这些明确的发现，我们的中心假设是MLL 4作为肿瘤抑制因子，通过以下途径抑制MB： 通过调节表观遗传标记激活肿瘤抑制基因的表达。在这里，我们建议 研究1）使用基因工程小鼠模型评估MLL 4在MB发展中的作用; 2） 确定M114损失驱动MB发生的分子机制; MB发生期间表观遗传标记的M114缺失。这些研究将揭示以前未知的 MB发病机制的表观遗传学机制，并为MB的发展提供有益的信息， MB疗法

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.