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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：
10809451
负责人：
Alla Grishok
金额：
$ 0.58万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-22 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10809451
关键词：
Animals Antibodies Antisense RNA Antiviral Response Binding Binding Proteins Bioethics 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 Experimental Genetics Fishes Future Gene Expression Gene Expression Regulation Gene Silencing Generations Genes Genetic Genetic Transcription Genomic approach Genomics Goals High School Student Histone H2A Histone H3 Homologous Gene Human Immunoprecipitation Laboratories Link Lysine Malignant Neoplasms Mammalian Cell Mammals Mediator Messenger RNA Methylation Methyltransferase MicroRNAs Modeling Molecular Mutation Names Nematoda Nuclear RNA Nucleotides PHD Finger Pathogenesis Pathway interactions Phenotype Plants Process Production Proteins Publishing RNA RNA Binding RNA Interference RNA-Protein Interaction 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 deep sequencing 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 undergraduate student

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. The project is not specific to bioethics research or capacity building in bioethics. Undergraduate and high school students will actively participate in the proposed research.

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性双链RNA产生和核的天然调节因子 RNA干扰。在这方面，我们重点关注RNA干扰与组蛋白之间的关系 H3 赖氨酸 79 DOT1L 甲基转移酶复合物。 DOT1L 交互伙伴 ZFP-1 之间的连接（哺乳动物中的 AF10）和线虫中的 RNAi 是在 13-15 年前通过基因实验提出的。到为了了解这种联系，我的实验室对 ZFP-1 和 DOT1L 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，而且提供了关于保守的新见解 DOT1L 在转录调控中的作用。 DOT1L 酶对于哺乳动物的发育至关重要，并且具有与白血病和乳腺癌的发病机制有关。然而，DOT1L 在基因中的确切作用监管不明确。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 甲基化全面抑制线虫中的非编码 RNA 转录，包括反义RNA和增强子RNA。我们的初步数据强烈表明异位 dsRNA 形成和小 RNA DOT1L 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 线虫中的小 RNA 分子； 2）探讨DOT1L抑制dsRNA功能的可能性在哺乳动物中是保守的，3) 研究 DOT1L 在哺乳动物中的转录调控机制使用线虫和斑马鱼系统进行开发。该项目并非专门针对生物伦理学研究或生物伦理学能力建设。本科和高中学生将积极参与拟议的研究。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small RNAs Worm Up Transgenerational Epigenetics Research.

DOI：
10.3390/dna1020005
发表时间：
2021-12
期刊：
DNA
影响因子：
0
作者：
Grishok A
通讯作者：
Grishok A

DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin.

DOT1L 通过促进染色质上的降解循环来刺激 MYC/Mondo 转录因子活性。

DOI：
10.1101/2024.02.06.579191
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Sepulveda,GianP;Gushchanskaia,EkaterinaS;Mora-Martin,Alexandra;Esse,Ruben;Nikorich,Iana;Ceballos,Ainhoa;Kwan,Julian;Blum,BenjaminC;Dholiya,Prakruti;Emili,Andrew;Perissi,Valentina;Cardamone,MariaD;Grishok,Alla
通讯作者：
Grishok,Alla

Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain.