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The role of DOT1L methyltransferase in controlling the noncoding transcriptome

DOT1L 甲基转移酶在控制非编码转录组中的作用

基本信息

批准号：
10460485
负责人：
Alla Grishok
金额：
$ 33万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460485
关键词：
Animals Antibodies Antisense RNA Antiviral Response Binding Binding Proteins Caenorhabditis elegans Cell Nucleus Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Complementary RNA Complex Congenital Abnormality Cytoplasm Data Development Developmental Gene Double-Stranded RNA Enhancers Enzymes Fishes Future Gene Expression Gene Expression Regulation Gene Silencing Generations Genes Genetic Genetic Transcription Genomic approach Genomics Goals Histone H2A Histone H3 Homologous Gene Human Immunoprecipitation Laboratories Lead Link Lysine Malignant Neoplasms Mammalian Cell Mammals Mediator of activation protein Messenger RNA Methylation Methyltransferase MicroRNAs Modeling Molecular Molecular Genetics Mutation Names Nematoda Nuclear RNA Nucleotides PHD Finger Pathogenesis Pathway interactions Phenotype Plant RNA Process Production Proteins Publishing RNA RNA Binding RNA Interference Research Role Small Interfering RNA Small RNA System Testing Titrations Transcriptional Activation Transcriptional Regulation Transgenes Untranslated RNA Variant Viral Virus Work Yeasts Zebrafish Zinc Fingers base chromatin remodeling deep sequencing experimental study genetic approach genome wide methylation global run on sequencing human disease insight interest leukemia loss of function mRNA Precursor malignant breast neoplasm mutant novel promoter protein complex recruit transcriptome

项目摘要

The broad goal of our research is to understand how gene expression is regulated during animal development. Our specific interest is in finding natural regulators of endogenous double-stranded RNA production and nuclear RNA interference. In this regard, we are focusing on the relationship between RNA interference and the histone H3 lysine 79 DOT1L methyltransferase complex. A connection between the DOT1L interacting partner ZFP-1 (AF10 in mammals) and RNAi in C. elegans was suggested by genetic experiments 13-15 years ago. To understand this connection, my laboratory undertook molecular and genomic studies of ZFP-1 and DOT1L. These studies not only confirmed the connection to RNAi, but also provided novel insights about the conserved role of DOT1L in transcription regulation. The DOT1L enzyme is essential for mammalian development and has been implicated in the pathogenesis of leukemia and breast cancer. However, the exact role of DOT1L in gene regulation is not clear. Preliminary work from our lab has begun to reveal this role; we have discovered that DOT1L and H3K79 methylation globally suppress non-coding RNA transcription in C. elegans, including that of antisense and enhancer RNAs. Our preliminary data strongly suggest ectopic dsRNA formation and small RNA production upon DOT1L loss-of-function. Our main goals are: 1) to detect and characterize these dsRNA and small RNA molecules in C. elegans; 2) to explore the possibility that the dsRNA suppressing function of DOT1L is conserved in mammals, and 3) to investigate the mechanism of transcription regulation by DOT1L in development using the C. elegans and zebrafish systems.

我们研究的主要目标是了解动物发育过程中基因表达是如何调节的。我们的具体兴趣是寻找内源双链 RNA 产生的天然调节因子核RNA干扰。在这方面，我们重点关注RNA干扰与RNA干扰之间的关系。组蛋白 H3 赖氨酸 79 DOT1L 甲基转移酶复合物。 DOT1L 交互之间的连接 13-15 年遗传实验表明秀丽隐杆线虫中存在伴侣 ZFP-1（哺乳动物中的 AF10）和 RNAi 前。为了了解这种联系，我的实验室对 ZFP-1 和 DOT1L。这些研究不仅证实了与 RNAi 的联系，而且提供了关于 RNAi 的新见解。 DOT1L 在转录调控中的保守作用。 DOT1L 酶对于哺乳动物至关重要的发展，并与白血病和乳腺癌的发病机制有关。然而，确切的 DOT1L 在基因调控中的作用尚不清楚。我们实验室的初步工作已经开始揭示这一作用；我们发现 DOT1L 和 H3K79 甲基化全面抑制 C. 线虫，包括反义RNA和增强子RNA。我们的初步数据强烈表明异位 dsRNA DOT1L 功能丧失后的形成和小 RNA 的产生。我们的主要目标是：1）检测和表征线虫中的这些 dsRNA 和小 RNA 分子； 2）探索dsRNA的可能性 DOT1L 的抑制功能在哺乳动物中是保守的，3) 研究转录机制使用线虫和斑马鱼系统开发中的 DOT1L 调节。