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

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

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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.

项目摘要这项研究的目的是了解mRNA翻译控制如何调节在正常和病理条件下的红细胞细胞。红细胞生成，红细胞的产生，对哺乳动物至关重要。这种细胞分化过程的故障可能会引起严重的贫血，并且是与大量人类血液学疾病有关，包括许多骨髓衰竭综合征，例如骨髓增生综合征。那是表征控制的分子机制红细胞生成既具有生物学和临床意义。以前的研究表征了许多控制红细胞分化的转录调节网络。另外，转录组学红细胞生成期间的动态已经进行了广泛的调查。这些RNA变化是“读取”和由转化设备，核糖体解释，在分化的红细胞细胞中产生适当的然而，蛋白质量仍然很大程度上是未知的。最近，我们发现了末端红细胞生成期间的蛋白质合成，并通过平行RNA和核糖体分析原代红斑。在不同发育阶段的细胞。具体而言，在末端红细胞生成期间，我们确定了数百个差异翻译的mRNA及其3'未翻译区域具有显着富集的结合基序几种红斑特异性的RNA结合蛋白，暗示翻译的调节网络。而且，我们发现了新颖的翻译法规形式，包括上游开放阅读框的动态使用，替代翻译终止和多生育复合物的化学计量合成。这些结果强烈主张动态翻译控制在红血病中的关键作用。有趣的是，突变中的突变细胞平移仪的几个组成部分，核糖体，可能引起几种人遗传具有无效的红细胞生成的疾病，例如钻石 - 黑色贫血和5Q- 综合征。这些临床观察结果凸显了研究红细胞翻译法规的重要性细胞分化。在这项研究中，我们将：a）表征由密钥介导的翻译调节网络正常红细胞生成中的红细胞特异性RNA结合蛋白； b）确定疾病相关的方式核糖体蛋白突变改变了红细胞细胞中的mRNA翻译。这项研究的结果不仅会填补红细胞生成中的重要知识差距，但也将提供重要的分子见解核糖体病，并有可能识别这些人类疾病的治疗靶标。