The role of DOT1L methyltransferase in controlling the noncoding transcriptome

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生产的天然调节器和 核RNA干扰。在这方面，我们正在重点研究RNA干扰和 组蛋白H3赖氨酸79 DOT1L甲基转移酶复合体。DOT1L交互之间的连接 13-15年的遗传学实验表明，线虫中存在ZFP-1(哺乳动物中的AF10)和RNAi伴侣 那是以前的事了。为了了解这种联系，我的实验室进行了ZFP-1和ZFP-1的分子和基因组研究。 DOT1L.这些研究不仅证实了与RNAi的联系，而且还提供了关于 DOT1L在转录调控中的保守作用。DOT1L酶对哺乳动物来说是必不可少的 发展，并已牵涉到白血病和乳腺癌的发病机制。然而，准确的 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角色；我们 发现DOT1L和H3K79甲基化在整体上抑制了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 DOT1L功能丧失时的形成和小RNA的产生。我们的主要目标是：1)检测和 鉴定这些dsRNA和线虫中的小RNA分子；2)探索dsRNA 抑制DOT1L的功能在哺乳动物中是保守的，3)研究转录机制 在使用线虫和斑马鱼系统的开发中由DOT1L进行调节。

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.