Studies of mRNA translational regulations in erythropoiesis

红细胞生成过程中mRNA翻译调控的研究

基本信息

批准号：
10181022
负责人：
Wenqian Hu
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181022
关键词：
3&apos Untranslated Regions Anemia Binding Binding Sites Biological Cell Differentiation process Cell Proliferation Clinical Complex Development Diamond-Blackfan anemia Disease Dysmyelopoietic Syndromes Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Event Functional disorder Gene Proteins Genetic Diseases Genetic Transcription Genetic Translation Genetic study Goals Hematological Disease Hematopoiesis High-Throughput Nucleotide Sequencing Human Human Genetics Immunoprecipitation Inherited Knock-out Knowledge Mammals Mediating Messenger RNA Molecular Mutation Open Reading Frames Pathologic Play Production Protein Biosynthesis Proteins RNA RNA-Binding Proteins Regulation Ribosomal Proteins Ribosomes Role Surveys Syndrome Testing Translating Translational Regulation Translations base bone marrow failure syndrome chromosome 5q loss clinically significant crosslink erythroid differentiation human disease in vivo insight mouse genetics novel protein complex ribosome profiling therapeutic target transcriptomics

项目摘要

PROJECT SUMMARY The goal of this study is to understand how mRNA translational control regulates the terminal differentiation of erythroid cells under both normal and pathological conditions. Erythropoiesis, the production of red blood cells, is essential to mammals. Malfunction of this cell differentiation process can cause severe anemias and is associated with a large number of human hematological disorders, including many bone marrow failure syndromes such as the myelodysplastic syndrome. Thus, characterizing the molecular mechanisms controlling erythropoiesis is of both biological and clinical significance. Previous studies have characterized many transcriptional regulatory networks controlling the erythroid cell differentiation. In addition, the transcriptomic dynamics during erythropoiesis have been extensively surveyed. How these RNA changes are “read” and interpreted by the translational apparatus, the ribosome, in the differentiating erythroid cells to generate proper amounts of proteins, however, is still largely unknown. Recently, we uncovered widespread regulations of protein synthesis during terminal erythropoiesis by parallel RNA and ribosome profiling on primary erythroid cells at different developmental stages. Specifically, during terminal erythropoiesis, we identified hundreds of differentially translated mRNAs, and their 3' untranslated regions have significantly enriched binding motifs of several erythroid-specific RNA-binding proteins, implying translational regulatory networks. Moreover, we found novel forms of translational regulations including dynamic usage of upstream open reading frames, alternative translation terminations, and stoichiometric synthesis of multi-subunit complexes. These results strongly argue for critical roles of dynamic translational control in erythropoiesis. Interestingly, mutations in several components of the cellular translational apparatus, the ribosome, can cause several human genetic diseases with manifestations of ineffective erythropoiesis, such as the Diamond-Blackfan anemia and the 5q- syndrome. These clinical observations highlight the importance of studying translational regulations in erythroid cell differentiation. In this study, we will: a) characterize the translational regulatory networks mediated by key erythroid-specific RNA-binding proteins in normal erythropoiesis; b) determine how disease-associated ribosomal protein mutations alter mRNA translation in erythroid cells. The results from this study will not only fill an important knowledge gap in erythropoiesis, but also will provide important molecular insights into ribosomopathies and potentially identify therapeutic targets for these human diseases.

项目概要本研究的目的是了解 mRNA 翻译控制如何调节细胞的终末分化正常和病理条件下的红细胞生成，红细胞的产生，对于哺乳动物来说至关重要。该细胞分化过程的故障会导致严重的贫血。与许多人类血液疾病有关，包括许多骨髓衰竭因此，表征了控制骨髓增生异常综合征的分子机制。红细胞生成具有生物学和临床意义。转录调控网络控制红细胞分化。红细胞生成过程中的动态已被广泛研究，以及如何“读取”这些 RNA 变化。由翻译装置核糖体在分化的红系细胞中解释以产生适当的然而，蛋白质的含量在很大程度上仍然未知。最近，我们发现了广泛的调控。通过初级红细胞上的平行 RNA 和核糖体分析分析终末红细胞生成过程中的蛋白质合成具体来说，在终末红细胞生成过程中，我们鉴定了数百个细胞。差异翻译的 mRNA，其 3' 非翻译区具有显着富集的结合基序几种红细胞特异性 RNA 结合蛋白，暗示翻译调控网络。发现了翻译规则的新颖形式，包括上游开放阅读框架的动态使用，替代翻译终止以及多亚基复合物的化学计量合成。强烈主张动态翻译控制在红细胞生成中的关键作用。细胞翻译装置的几个组成部分，即核糖体，可以引起多种人类遗传具有无效红细胞生成表现的疾病，例如 Diamond-Blackfan 贫血和 5q- 这些临床观察强调了研究红细胞转化调控的重要性。在这项研究中，我们将：a）表征关键介导的翻译调控网络。正常红细胞生成中的红细胞特异性 RNA 结合蛋白 b) 决定如何与疾病相关；核糖体蛋白突变改变红细胞中的 mRNA 翻译这项研究的结果不仅将填补这一空白。红细胞生成方面的一个重要知识空白，但也将为以下方面提供重要的分子见解核糖体病并可能确定这些人类疾病的治疗靶点。