Analysis of mRNA Polyadenylation across Species and Tissues

跨物种和组织的 mRNA 多腺苷酸化分析

• 批准号: 8068636
• 负责人: BIN TIAN
• 金额: $ 29.81万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068636
• 关键词: 3' Untranslated Regions; Address; Affect; Biochemical; Biological; Biological Assay; Cell Line; Classification; Code; Complementary DNA; Computational Molecular Biology; DNA Microarray Chip; Data; Databases; Elements; Event; Evolution; Exons; Expressed Sequence Tags; Frequencies; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genetic Polymorphism; Genome; Goals; Human; Indium; Introns; Light; Machine Learning; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; MicroRNAs; Modeling; Molecular Biology; Molecular Biology Techniques; Mus; Mutagenesis; Mutation; Pattern; Phylogenetic Analysis; Poly A; Polyadenylation; Polyadenylation Pathway; Proteins; RNA; RNA Binding; RNA Interference; RNA Splicing; RNA-Binding Proteins; Regulation; Regulatory Element; Relative (related person); Reporter; Site; Statistical Models; Structure; System; Technology; Tissues; Trees; Untranslated Regions; Validation; Variant; base; human disease; improved; preference; research study; serial analysis of gene expression; tool

DESCRIPTION (provided by applicant): mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs. Altered polyadenylation activity caused by genetic mutation has been implicated in a growing number of human diseases. Over half of the human genes contain multiple polyadenylation sites [poly(A) sites] supported by cDNA/EST sequences. The polyadenylation pattern in the 3'- most exon defines the 3' UnTranslated Region (UTR), which contains various cis regulatory elements for mRNA metabolism, such as microRNA (miRNA) target sites and AU-rich elements (AUEs). In addition, a large fraction of human genes have polyadenylation events in introns, leading to mRNA variants with different protein coding sequence and indicating dynamic interplay between polyadenylation and splicing. Regulation of gene expression by polyadenylation has been characterized only for a handful of model genes, and its mechanism is poorly understood on the systems level. The long-term goal is to understand the mechanisms by which mRNA polyadenylation regulates gene expression in eukaryotic genomes. There are two specific aims in this project: 1) To accurately predict poly(A) sites across metazoan species using their corresponding cis elements; 2) To quantitatively model poly(A) site usage and selection across human and mouse tissues. We will combine computational and molecular biology techniques to address these issues. The results will improve gene annotation in metazoan species, uncover gene regulation events mediated by alternative polyadenylation, elucidate 3' UTR evolution, shed light on the mechanisms of polyadenylation, and provide valuable tools to examine human mutations and polymorphisms that affect poly(A) sites. NARRATIVE mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs. Altered polyadenylation activity caused by genetic mutation has been implicated in a growing number of human diseases. Over half of the human genes contain multiple polyadenylation sites [poly(A) sites] supported by cDNA/EST sequences. The polyadenylation pattern in the 3'- most exon defines the 3' UnTranslated Region (UTR), which contains various cis regulatory elements for mRNA metabolism, such as microRNA (miRNA) target sites and AU-rich elements (AUEs). In addition, a large fraction of human genes have polyadenylation events in introns, leading to mRNA variants with different protein coding sequence and indicating dynamic interplay between polyadenylation and splicing. Regulation of gene expression by polyadenylation has been characterized only for a handful of model genes, and its mechanism is poorly understood on the systems level. The long term goal is to understand the mechanisms by which mRNA polyadenylation regulates gene expression in eukaryotic genomes. There are two specific aims in this project: 1) To accurately predict poly(A) sites across metazoan species using their corresponding cis elements; 2) To quantitatively model poly(A) site usage and selection across human and mouse tissues. We will combine computational and molecular biology techniques to address these issues. The results will improve gene annotation in metazoan species, uncover gene regulation events mediated by alternative polyadenylation, elucidate 3' UTR evolution, shed light on the mechanisms of polyadenylation, and provide valuable tools to examine human mutations and polymorphisms that affect poly(A) sites.

描述（由申请人提供）：mRNA聚腺苷酸化是几乎所有真核mRNA成熟的重要步骤。由遗传突变引起的多腺苷酸化活性改变与越来越多的人类疾病有关。超过一半的人基因包含由cDNA/EST序列支持的多个聚腺苷酸位点[poly（a）位点]。 3'-外显子中的聚腺苷酸化模式定义了3'未翻译区（UTR），其中包含MRNA代谢的各种顺式调节元素，例如microRNA（miRNA）靶位点和富含AU的元素（AUE）。此外，大量的人基因在内含子中具有聚腺苷酸化事件，从而导致具有不同蛋白质编码序列的mRNA变体，并指示聚腺苷酸化和剪接之间的动态相互作用。通过少数模型基因来调节基因表达的调节，其机制在系统级别上对其机理的理解很少。长期目标是了解mRNA聚腺苷酸化调节真核基因组中基因表达的机制。该项目中有两个具体的目的：1）使用相应的CIS元素准确预测跨后生动物的poly（a）位点； 2）定量建模poly（a）位点的用法和跨人体组织的选择。我们将结合计算和分子生物学技术来解决这些问题。该结果将改善后生动物物种的基因注释，发现由替代聚腺苷酸化介导的基因调节事件，阐明3'UTR进化，阐明了聚腺苷酸化的机制，并提供了检查人类突变和多态性影响聚（a）位点的有价值的工具。叙事mRNA聚腺苷酸化是几乎所有真核mRNA成熟的重要步骤。由遗传突变引起的多腺苷酸化活性改变与越来越多的人类疾病有关。超过一半的人基因包含由cDNA/EST序列支持的多个聚腺苷酸位点[poly（a）位点]。 3'-外显子中的聚腺苷酸化模式定义了3'未翻译区（UTR），其中包含MRNA代谢的各种顺式调节元素，例如microRNA（miRNA）靶位点和富含AU的元素（AUE）。此外，大量的人基因在内含子中具有聚腺苷酸化事件，从而导致具有不同蛋白质编码序列的mRNA变体，并指示聚腺苷酸化和剪接之间的动态相互作用。通过少数模型基因来调节基因表达的调节，其机制在系统级别上对其机理的理解很少。长期目标是了解mRNA聚腺苷酸化调节真核基因组中基因表达的机制。该项目中有两个具体的目的：1）使用相应的CIS元素准确预测跨后生动物的poly（a）位点； 2）定量建模poly（a）位点的用法和跨人体组织的选择。我们将结合计算和分子生物学技术来解决这些问题。该结果将改善后生动物物种的基因注释，发现由替代聚腺苷酸化介导的基因调节事件，阐明3'UTR进化，阐明了聚腺苷酸化的机制，并提供了检查人类突变和多态性影响聚（a）位点的有价值的工具。