Analysis of mRNA Polyadenylation across Species and Tissues

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由cDNA/EST序列支持的多聚腺苷酸化位点[poly（A）sites]。最3 '端外显子中的多腺苷酸化模式定义了3'非翻译区（UTR），其包含用于mRNA代谢的各种顺式调节元件，如微小RNA（miRNA）靶位点和富含AU的元件（AUE）。此外，大部分人类基因在内含子中具有多聚腺苷酸化事件，导致具有不同蛋白质编码序列的mRNA变体，并表明多聚腺苷酸化和剪接之间的动态相互作用。通过多聚腺苷酸化调节基因表达的特征仅在于少数模型基因，并且其机制在系统水平上知之甚少。长期目标是了解mRNA多聚腺苷酸化调节真核基因组中基因表达的机制。该项目有两个具体目标：1）使用相应的顺式元件准确预测多聚腺苷酸位点在后生动物物种中的分布; 2）定量模拟多聚腺苷酸位点在人类和小鼠组织中的使用和选择。我们将结合联合收割机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酸化介导的基因调控事件，阐明3' UTR的进化，阐明多聚腺苷酸化的机制，并提供有价值的工具来检查人类突变和多态性，影响聚（A）位点。mRNA多聚腺苷酸化是几乎所有真核生物mRNA成熟的重要步骤。由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由cDNA/EST序列支持的多聚腺苷酸化位点[poly（A）sites]。最3 '端外显子中的多腺苷酸化模式定义了3'非翻译区（UTR），其包含用于mRNA代谢的各种顺式调节元件，如微小RNA（miRNA）靶位点和富含AU的元件（AUE）。此外，大部分人类基因在内含子中具有多聚腺苷酸化事件，导致具有不同蛋白质编码序列的mRNA变体，并表明多聚腺苷酸化和剪接之间的动态相互作用。通过多聚腺苷酸化调节基因表达的特征仅在于少数模型基因，并且其机制在系统水平上知之甚少。长期目标是了解mRNA多聚腺苷酸化调节真核基因组中基因表达的机制。该项目有两个具体目标：1）使用相应的顺式元件准确预测多聚腺苷酸位点在后生动物物种中的分布; 2）定量模拟多聚腺苷酸位点在人类和小鼠组织中的使用和选择。我们将结合联合收割机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酸化介导的基因调控事件，阐明3' UTR的进化，阐明多聚腺苷酸化的机制，并提供有价值的工具来检查人类突变和多态性，影响聚（A）位点。

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.