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.

我们研究的主要目标是了解在动物发育过程中基因表达是如何被调控的。