Post-transcriptional gene regulation

转录后基因调控

• 批准号: 9256511
• 负责人: DAVID P BARTEL
• 金额: $ 71.29万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256511
• 关键词: Area; Biochemical; Biochemical Genetics; Biogenesis; Biological Process; Cells; Cleaved cell; Complex; Congenital Abnormality; Coupling; Defect; Development; Disease; Embryo; Embryonic Development; Enzymes; Fertility; Gene Expression Regulation; Gene Silencing Pathway; Genes; Genetic; Genetic Transcription; Human; Length; Malignant Neoplasms; Messenger RNA; Methods; MicroRNAs; Molecular; Molecular Computations; Pathway interactions; Patients; Play; Poly(A) Tail; Principal Investigator; Process; Proteins; RNA Interference; Recruitment Activity; Regulation; Regulator Genes; Regulatory Pathway; Reporter Genes; Resources; Role; Small Interfering RNA; Tail; Transcript; Translational Repression; Untranslated RNA; Viral Cancer; Virus; Virus Diseases; Yeasts; Zebrafish; experimental study; gastrulation; gene function; genetic approach; human disease; improved; insight; mRNA Stability; novel therapeutics; programs; public health relevance

 DESCRIPTION (provided by applicant): Much of eukaryotic gene regulation occurs post-transcriptionally, through differential mRNA stability and/or translational efficiency. The researc of this proposal seeks to answer fundamental questions within three interrelated areas of post-transcriptional gene control: microRNAs, RNA interference, and mRNA poly (A) tails. MicroRNAs (miRNAs) are ~22-nt RNAs that pair to mRNAs to direct their destabilization and translational repression. More than 600 miRNA genes have been identified in humans, and because most human genes are conserved targets of miRNAs, it is no surprise that miRNAs play important roles in mammalian development and human diseases, including viral infections and cancers. Molecular, computational, and structural approaches will be used to determine 1) how the microRNA-biogenesis machinery recognizes the cellular transcripts that are to be processed into microRNAs, 2) the biochemical basis of miRNA-target recognition and improved methods for predicting the most repressed targets, 3) the reason that mRNAs from reporter genes are repressed differently than those from endogenous genes, and 4) the mechanism and the biological function of the regulation of a miRNA by a long noncoding RNA. Results of these studies are expected to enhance the fundamental understanding of this important class of gene-regulatory molecules and provide resources helpful for many biologists, including those studying the roles of miRNAs in human diseases. RNA interference (RNAi) is a gene-regulatory pathway that many eukaryotic species use to silence transposons and viruses. In this pathway, short interfering RNAs (siRNAs) resembling miRNAs are loaded into Argonaute, which is an effector protein that cleaves transcripts with extensive complementarity to the siRNA. Genetic, structural, biochemical, and molecular approaches will be used to 1) identify and study additional proteins required for efficient RNAi in yeast, 2) determine how the siRNA-Argonaute complex forms and how it recognizes mRNA targets, and 3) investigate the unusual activities of zebrafish Argonaute. Results are expected to provide mechanistic insight into this gene-silencing pathway fundamental for defending many eukaryotic species against transposons and viruses, with practical implications for biologists using this pathway to study gene function, as well as those harnessing it to treat patients. mRNA poly (A) tails are important for mRNA stability and translational efficiency, and metazoan miRNAs usually act by recruiting enzymes that shortening poly (A) tails. The relationship between poly (A)-tail length and translational efficiency changes as the embryo develops. Molecular, computational, biochemical, and genetic approaches will be used to determine how coupling between tail length and translational efficiency is established before gastrulation and why it disappears after gastrulation. Results are expected to provide fundamental insight into translational control and embryonic development, with potential implications for human fertility, developmental defects, or other diseases. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

 描述（由申请人证明）：转录后的大部分真核基因，Thuce差异mRNA稳定性和 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或或授予该提案的研究。 RNA干扰和mRNA Poly（A）尾巴（miRNA）是MRNA的22-nt RNA，以指导其不可能和转化的RNA。 ，毫不奇怪的是，miRNA在哺乳动物的发育和人类呼吸和癌症中起着重要作用，将使用分子，计算和结构方法来确定1）将原始的转录本应原发作，2） - 识别和改进的方法提出了ST抑制靶标的，3）由内源基因抑制的mRNA的mRNA，以及4）4）长期非编码RNA的机制和法规。重要的基因常规分子，并为许多在人类探索中的生物学家（RNAi）提供了有用的资源。类似于miRNA的siRNA被加载到用siRNA裂解转录本的Argonaute蛋白。 3）斑马鱼Argona的异常活动。 Tazoan mirnas通过募集py（a）尾巴的关系来招募酶 预计将提供转化控制和胚胎发育，对人类的感觉缺陷或其他疾病有潜在的影响。