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

基本信息

批准号：
10159217
负责人：
Min Gyu Lee
金额：
$ 36.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2017-06-07 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159217
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 MLL2 gene Malignant - descriptor Mediating Methylation Methyltransferase Mixed-Lineage Leukemia Molecular 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 Suppressor-Effector T-Lymphocytes TP53 gene Testing Therapeutic Transcription Coactivator Transcriptional Regulation Tretinoin Tumor Suppressor Genes Tumor Suppressor Proteins Western Blotting anticancer research base design driving force epigenetic regulation genetic corepressor histone methylation histone methyltransferase histone modification human model human stem cells in vivo innovation insight medulloblastoma mouse model mutant nestin protein novel p38 Mitogen Activated Protein Kinase promoter ras Guanine Nucleotide Exchange Factors ras-GRF1 stem cells tumor tumorigenic

项目摘要

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 通过以下方式激活多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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.

DOI：
10.1016/j.celrep.2020.108293
发表时间：
2020-10-20
期刊：
Cell reports
影响因子：
8.8
作者：
Maitituoheti M;Keung EZ;Tang M;Yan L;Alam H;Han G;Singh AK;Raman AT;Terranova C;Sarkar S;Orouji E;Amin SB;Sharma S;Williams M;Samant NS;Dhamdhere M;Zheng N;Shah T;Shah A;Axelrad JB;Anvar NE;Lin YH;Jiang S;Chang EQ;Ingram DR;Wang WL;Lazar A;Lee MG;Muller F;Wang L;Ying H;Rai K
通讯作者：
Rai K

Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumors.