Transcriptome processing networks in skeletal muscle: mechanisms and functions

骨骼肌转录组处理网络：机制和功能

• 批准号: 8235082
• 负责人: Thomas A Cooper
• 金额: $ 35.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235082
• 关键词: Adult; Affect; Alleles; Alternative Splicing; Birds; Caenorhabditis elegans; Candidate Disease Gene; Cell Line; Cell physiology; DNA Microarray Chip; Detection; Development; Disease; Event; Family; Foxes; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genetic Translation; Goals; Human; Investigation; Knock-out; Knowledge; Maintenance; Mammals; Mediating; Messenger RNA; Modeling; Molecular; Mus; Muscle; Muscle function; Myoblasts; Myogenin; Myopathy; Nuclear; Output; Phenotype; Physiological; Play; Polyadenylation; Post-Transcriptional Regulation; Process; Proliferating; Protein Binding; Protein Isoforms; Proteins; Proteome; RNA Interference; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Reporter; Role; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Tamoxifen; Time; Tissues; Transcriptional Regulation; Untranslated Regions; genome wide association study; in vivo; interest; mRNA Precursor; mRNA Stability; mammalian genome; novel therapeutics; prevent; programs; public health relevance; repaired; response; satellite cell; skeletal muscle differentiation; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): In addition to transcriptional regulation of gene output, mammalian genomes produce extensive transcriptome and proteome diversity by alternative splicing and selection of alternative 3' mRNA ends during pre-mRNA processing. As for transcription, transcriptome processing is extensively regulated in response to dynamic physiological needs. The regulation of transcriptome processing involves interconnected networks controlled by RNA binding proteins that bind to preferred sequence motifs within the pre-mRNA near the sites of regulated processing. The long term goal of this project is to determine the extent, regulatory mechanisms, and functional consequences of transcriptome processing in adult skeletal muscle. The disruption of transcriptome processing networks contributes to disease in skeletal muscle yet little is known regarding the extent or functions of normal regulation. In the first part of this proposal, we will identify the regulatory networks controlled by the Fox family of RNA binding proteins in skeletal muscle and determine their functions during myoblast differentiation. We will use tissue specific and inducible knock outs of the two Fox genes expressed in skeletal muscle to determine the functions of the regulatory networks in myofibers and satellite cells in adult skeletal muscle. In the second part of the proposal, we will identify additional regulatory networks operative during myoblast differentiation using a bichromatic splicing reporter in high throughput RNAi screens. Knowledge gained will be directed toward understanding the roles of these networks in adult skeletal muscle. The results will provide a new understanding of the role of nuclear post-transcriptional regulation in the diverse homeostatic functions of adult skeletal muscle and its capacity for repair. This understanding is important for development and application of novel therapeutic strategies to conditions that negatively affect skeletal muscle function. PUBLIC HEALTH RELEVANCE: Post-transcriptional regulation of gene expression, such as alternative splicing and 3' end processing, play a large role in controlling gene expression. This proposal studies the mechanisms of alternative splicing and 3' end processing during skeletal muscle differentiation and in adult skeletal muscle tissue. This information will be used to understand normal processes in skeletal muscle useful for future development of therapeutic approaches to reverse or circumvent disease.

描述（由申请人提供）：除了基因输出的转录调节之外，哺乳动物基因组通过在前mRNA加工过程中的选择性剪接和选择性3'mRNA末端的选择产生广泛的转录组和蛋白质组多样性。至于转录，转录组处理根据动态生理需求受到广泛调节。转录组加工的调节涉及由 RNA 结合蛋白控制的互连网络，这些蛋白与受调节加工位点附近的前 mRNA 内的首选序列基序结合。该项目的长期目标是确定成人骨骼肌转录组处理的程度、调节机制和功能后果。转录组处理网络的破坏会导致骨骼肌疾病，但对于正常调节的程度或功能知之甚少。在本提案的第一部分，我们将鉴定骨骼肌中由RNA结合蛋白Fox家族控制的调控网络，并确定它们在成肌细胞分化过程中的功能。我们将利用骨骼肌中表达的两个 Fox 基因的组织特异性和诱导性敲除来确定成人骨骼肌中肌纤维和卫星细胞调节网络的功能。在该提案的第二部分，我们将在高通量 RNAi 筛选中使用双色剪接报告基因确定在成肌细胞分化过程中起作用的其他调控网络。获得的知识将用于理解这些网络在成人骨骼肌中的作用。这些结果将为核转录后调节在成人骨骼肌多种稳态功能及其修复能力中的作用提供新的认识。这种理解对于开发和应用新的治疗策略来治疗对骨骼肌功能产生负面影响的疾病非常重要。 公共卫生相关性：基因表达的转录后调控，例如可变剪接和 3' 末端加工，在控制基因表达方面发挥着重要作用。该提案研究了骨骼肌分化过程中和成人骨骼肌组织中选择性剪接和 3' 末端加工的机制。这些信息将用于了解骨骼肌的正常过程，有助于未来开发逆转或规避疾病的治疗方法。