Analysis of mRNA Polyadenylation across Species and Tissues

描述（由申请人提供）：mRNA聚腺苷化是几乎所有真核生物mRNA成熟的必要步骤。基因突变引起的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cDNA/EST序列支持的聚腺苷化位点[聚(A)位点]。3‘-最外显子的多聚腺苷化模式定义了3’非翻译区（UTR），其中包含各种mRNA代谢的顺式调控元件，如microRNA （miRNA）靶位点和au富元件（aue）。此外，很大一部分人类基因在内含子中有多聚腺苷化事件，导致mRNA变异具有不同的蛋白质编码序列，表明多聚腺苷化和剪接之间存在动态相互作用。聚腺苷酸化对基因表达的调控仅在少数模式基因中被表征，其在系统水平上的机制尚不清楚。长期目标是了解mRNA聚腺苷化调节真核生物基因组基因表达的机制。本项目有两个具体目标：1)利用其相应的顺式元素准确预测后生动物物种的poly(A)位点；2)定量模拟人类和小鼠组织中poly(A)位点的使用和选择。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，揭示由选择性多聚腺苷化介导的基因调控事件，阐明3' UTR进化，揭示多聚腺苷化的机制，并为研究影响多聚(A)位点的人类突变和多态性提供有价值的工具。mRNA聚腺苷化是几乎所有真核生物mRNA成熟的必要步骤。基因突变引起的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cDNA/EST序列支持的聚腺苷化位点[聚(A)位点]。3‘-最外显子的多聚腺苷化模式定义了3’非翻译区（UTR），其中包含各种mRNA代谢的顺式调控元件，如microRNA （miRNA）靶位点和au富元件（aue）。此外，很大一部分人类基因在内含子中有多聚腺苷化事件，导致mRNA变异具有不同的蛋白质编码序列，表明多聚腺苷化和剪接之间存在动态相互作用。聚腺苷酸化对基因表达的调控仅在少数模式基因中被表征，其在系统水平上的机制尚不清楚。长期目标是了解mRNA聚腺苷化调节真核生物基因组基因表达的机制。本项目有两个具体目标：1)利用其相应的顺式元素准确预测后生动物物种的poly(A)位点；2)定量模拟人类和小鼠组织中poly(A)位点的使用和选择。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，揭示由选择性多聚腺苷化介导的基因调控事件，阐明3' UTR进化，揭示多聚腺苷化的机制，并为研究影响多聚(A)位点的人类突变和多态性提供有价值的工具。

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.