Analysis of mRNA Polyadenylation across Species and Tissues

描述(申请人提供)：信使核糖核酸多聚腺苷酸化是几乎所有真核生物信使核糖核酸成熟的必要步骤。基因突变引起的多聚腺苷酸化活性改变与越来越多的人类疾病有关。超过一半的人类基因含有多个由cDNAEST序列支持的多聚腺苷酸化位点[PolyA位点]。3‘-最大外显子上的多聚腺苷酸化模式定义了3’非翻译区(UTR)，它包含了mRNA代谢的各种顺式调控元件，如microRNA(MiRNA)靶点和富含AU的元件(AUES)。此外，很大一部分人类基因在内含子中存在多聚腺苷酸化事件，导致不同蛋白质编码序列的mRNA变异，表明多腺苷化和剪接之间存在动态相互作用。多聚腺苷酸化对基因表达的调控只针对少数几个模型基因，其机制在系统水平上知之甚少。我们的长期目标是了解真核基因组中信使核糖核酸多糖化调控基因表达的机制。该项目有两个具体目标：1)使用相应的顺式元件准确预测后生动物物种中的聚(A)位点；2)对人和鼠组织中聚(A)位点的使用和选择进行定量建模。我们将结合计算和分子生物学技术来解决这些问题。这些结果将改善后生动物物种的基因注释，揭示由交替多聚腺苷酸化介导的基因调控事件，阐明3‘非编码区进化，阐明多腺苷酸化的机制，并为检测影响PolyA位点的人类突变和多态提供有价值的工具。叙述性信使核糖核酸化是几乎所有真核生物信使核糖核酸成熟的关键步骤。基因突变引起的多聚腺苷酸化活性改变与越来越多的人类疾病有关。超过一半的人类基因含有多个由cDNAEST序列支持的多聚腺苷酸化位点[PolyA位点]。3‘-最大外显子上的多聚腺苷酸化模式定义了3’非翻译区(UTR)，它包含了mRNA代谢的各种顺式调控元件，如microRNA(MiRNA)靶点和富含AU的元件(AUES)。此外，很大一部分人类基因在内含子中存在多聚腺苷酸化事件，导致不同蛋白质编码序列的mRNA变异，表明多腺苷化和剪接之间存在动态相互作用。多聚腺苷酸化对基因表达的调控只针对少数几个模型基因，其机制在系统水平上知之甚少。长期目标是了解真核基因组中信使核糖核酸多糖化调控基因表达的机制。该项目有两个具体目标：1)使用相应的顺式元件准确预测后生动物物种中的聚(A)位点；2)对人和鼠组织中聚(A)位点的使用和选择进行定量建模。我们将结合计算和分子生物学技术来解决这些问题。这些结果将改善后生动物物种的基因注释，揭示由交替多聚腺苷酸化介导的基因调控事件，阐明3‘非编码区进化，阐明多腺苷酸化的机制，并为检测影响PolyA位点的人类突变和多态提供有价值的工具。

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.