The let-7 Regulatory Network

let-7 监管网络

• 批准号: 9027441
• 负责人: Leemor Joshua-Tor
• 金额: $ 34.56万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027441
• 关键词: Address; Animals; Binding; Biochemical; Biogenesis; Cells; Chromatin Structure; Colorectal Cancer; Complex; Development; Down-Regulation; Enzymes; Exonuclease; Family; Funding; Gene Expression; Gene Silencing; Genome; Goals; Human; In Vitro; Link; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Messenger RNA; MicroRNAs; Modification; Molecular; Nephroblastoma; Oncogenes; Pathway interactions; Perlman syndrome; Plants; Play; Post-Transcriptional Regulation; Quality Control; RNA Degradation; RNA Interference; Regulation; Renal carcinoma; Request for Proposals; Role; Signal Transduction; Somatic Cell; Specificity; Stem cells; Structure; Tail; Tumor Suppressor Proteins; Uridine; base; biophysical techniques; cancer cell; embryonic stem cell; glucose metabolism; interest; mRNA Transcript Degradation; overexpression; pluripotency; public health relevance; repaired; tissue regeneration

 DESCRIPTION (provided by applicant) RNA interference (RNAi) plays an important role in development, post-transcriptional regulation of gene expression in plants and animals and can impact genome organization and chromatin structure. While many studies focus on the identification of microRNA (miRNA) targets and the various downstream mechanisms of gene silencing, here we are interested in the regulation of a particular miRNA, let-7. The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Alternatively, Lin28 overexpression is correlated with the onset of numerous cancers, while let-7, a tumor suppressor, silences several human oncogenes. The Lin28/let-7 pathway is like a bistable switch. Each molecule represses expression of the other, and once the cell changes its state, the result is differentiation, or if the switch is reversed, cancer. At t h e molecular l e e l , Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3' oligouridylation activity of TUT4 and/or TUT7. The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by the exonuclease Dis3L2. In somatic cells, in the absence of L i n 2 8 , TUT4/7 promotes let-7 biogenesis by catalyzing single uridine addition to a subset of pre-let-7 miRNAs. Here, we propose to study the molecular basis of Lin28 mediated recruitment of TUT4/7 to pre-let-7, the switch in TUT4/7 activity between a monouridylase in the absence of Lin28 and an oligouridylase in the presence of Lin28, and the subsequent degradation of pre-let-7 by Dis3L2. We will utilize a similar approach to initiate an understanding of the broader role of TUT4/7 in marking both miRNA and mRNA with untemplated uridines.

 描述（由申请人提供） RNA 干扰 (RNAi) 在动植物基因表达的发育和转录后调控中发挥着重要作用，并且可以影响基因组组织和染色质结构，而许多研究重点是 microRNA (miRNA) 靶标的识别和各种下游机制。基因沉默的研究中，我们对特定 miRNA let-7 的调节感兴趣。多能因子 Lin28 抑制哺乳动物 microRNA let-7 家族的生物发生。另外，Lin28 过度表达与多种癌症的发生相关，而肿瘤抑制因子 let-7 则可抑制多种人类癌基因。 -7 通路就像一个双稳态开关，每个分子都会抑制另一个分子的表达，一旦细胞改变其状态，就会导致分化，如果开关逆转，就会导致癌症。 , Lin28 与前体 let-7 (pre-let-7) 发夹结合，触发 3' 寡尿苷化活性 TUT4 和/或 TUT7。添加到 pre-let-7 上的oligoU 尾部充当衰减信号，因为它会被核酸外切酶 Dis3L2 快速降解。在缺乏 L i n 2 8 的情况下，TUT4/7 会促进 let。 -7 通过催化单个尿苷添加到 pre-let-7 miRNA 的子集上来实现生物发生在这里，我们建议研究 Lin28 介导的募集的分子基础。 TUT4/7 到 pre-let-7，TUT4/7 活性在不存在 Lin28 的情况下单尿苷酸化酶和存在 Lin28 的寡尿苷酸化酶之间的转换，以及随后由 Dis3L2 降解 pre-let-7。使用类似的方法来了解 TUT4/7 在用非模板尿苷标记 miRNA 和 mRNA 方面的更广泛作用。