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

• 批准号: 10581918
• 负责人: Alla Grishok
• 金额: $ 2.55万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10581918
• 关键词: Animals; Caenorhabditis elegans; Complex; Congenital Abnormality; Data; Development; Double-Stranded RNA; Enhancers; Enzymes; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Genomics; Goals; Histone H3; Laboratories; Lysine; Malignant Neoplasms; Mammals; Methyltransferase; Molecular; Nuclear RNA; Pathogenesis; Production; RNA; RNA Interference; Research; Role; Small RNA; System; Transcriptional Regulation; Untranslated RNA; Work; Zebrafish; experimental study; genome wide methylation; human disease; insight; interest; leukemia; loss of function; malignant breast neoplasm; novel; transcriptome

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.

我们研究的广泛目标是了解基因表达在动物发育过程中是如何调节的。 我们特别感兴趣的是寻找内源性双链RNA产生和核转录的天然调节因子。 RNA干扰在这方面，我们正在关注RNA干扰和组蛋白之间的关系， H3赖氨酸79 DOT 1 L甲基转移酶复合物。DOT 1 L相互作用伙伴ZFP-1之间的连接 (AF10在哺乳动物中）和在C.在13-15年前的遗传实验中，到 为了理解这种联系，我的实验室对ZFP-1和DOT 1 L进行了分子和基因组研究。 这些研究不仅证实了与RNAi的联系，而且还提供了关于保守基因的新见解。 DOT 1 L在转录调控中的作用。DOT 1 L酶是哺乳动物发育所必需的， 与白血病和乳腺癌的发病机制有关。然而，DOT 1 L在基因表达中的确切作用尚不清楚。 规则不明确。我们实验室的初步工作已经开始揭示这种作用;我们发现， DOT 1 L和H3 K79甲基化在整体上抑制C.优雅，包括 反义和增强子RNA。我们的初步数据强烈表明异位dsRNA的形成和小RNA DOT 1 L功能丧失后的生产。我们的主要目标是：1）检测和表征这些dsRNA， C. 2）探讨DOT 1 L的dsRNA抑制功能可能性 在哺乳动物中是保守的，3）研究DOT 1 L在哺乳动物中的转录调控机制， 开发利用C. elegans线虫and zebrafish斑马鱼systems系统.