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Modulation of Runx2 activity by arginine methylation

通过精氨酸甲基化调节 Runx2 活性

基本信息

批准号：
9903272
负责人：
Jian Xu
金额：
$ 20.63万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903272
关键词：
Address Affect Affinity Alanine Arginine Binding Biology Bone Development Bone Injury C-terminal Calvaria Cell Culture System Cell Culture Techniques Cell Differentiation process Cell Proliferation ChIP-seq Cleidocranial Dysplasia Collaborations Complex Congenital Abnormality Data Development Embryo Enhancers Focus Groups Future Genes Genetic Transcription Genomics Homeostasis Human Impairment Intervention Lead Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Metabolic Bone Diseases Metabolism Methylation Methyltransferase Modeling Modification Molecular Mus Mutate Natural regeneration Organ Culture Techniques Osteocalcin Osteogenesis Pathway interactions Post-Translational Protein Processing Process Protein Methylation Protein-Arginine N-Methyltransferase Proteins Proteomics Regulation Reporting Repression Research Design Role Runx2 protein Signal Pathway Signal Transduction Site Testing Therapeutic Tooth structure Transactivation Transcription Coactivator Transcriptional Activation Transforming Growth Factor beta base bone bone cell bone loss cancer cell cell motility cofactor cranium experience genetic corepressor improved in vivo inhibitor/antagonist knowledge translation migration mouse genetics mutant novel novel therapeutic intervention osteoblast differentiation osteogenic promoter protein function protein protein interaction repaired response skeletal disorder spatiotemporal transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Protein arginine methylation is a rapidly growing field with increasingly recognized importance in cancer, but almost nothing is known about this mechanism in bone. This proposal is based on novel discoveries on the arginine methylation of Runx2. We have identified two protein arginine methyltransferases that methylate Runx2 on four defined arginine residues. By mutating these residues to alanine that mimic the methylation- deficient state, we have demonstrated the requirement for Runx2 arginine methylation in Runx2-mediated cancer cell motility. Here, we will investigate Runx2 arginine methylation in the context of its canonical role in osteoblast differentiation and bone formation. Aim 1 is to characterize the temporal arginine methylation of Runx2 in osteogenic cell culture models. We will also compare the osteogenic potentials of WT Runx2 versus unmethylatable mutant Runx2, and the consequences of manipulating methyltransferases that mediate Runx2 methylation. Aim 2 addresses the role of Runx2 arginine methylation in modulating the physical and functional interaction with BMP-Smads pathway. Finally, Aim 3 is to define the arginine methylation of Runx2, and the expression of methyltransferases that mediate Runx2 methylation during skull development in vivo, and to compare the osteogenic potential of WT versus unmethylatable Runx2 in calvarial organ cultures. Overall, this proposal addresses the hypothesis that arginine methylation is required for Runx2 activity during osteogenic differentiation and essential for BMP-Smad signaling response. Additionally, we have incorporated in the study design genomic and proteomic analyses to facilitate unbiased discoveries of Runx2 protein-protein interactions, Runx2 genomic targets and Runx2-regulated genes that are impacted by its arginine methylation. In the long run, we envision translation of knowledge acquired in this exploratory project to improve the understanding of bone development, homeostasis and regeneration, and provide novel therapeutic approaches to tackle skeletal disorders.

项目总结/摘要蛋白质精氨酸甲基化是一个快速发展的领域，在癌症中的重要性日益得到认可，但对骨骼中的这种机制几乎一无所知。这项建议是基于新的发现， Runx 2的精氨酸甲基化。我们已经确定了两种蛋白质精氨酸甲基转移酶， Runx 2上的四个确定的精氨酸残基。通过将这些残基突变为丙氨酸来模拟甲基化- 在缺乏状态下，我们已经证明了Runx 2介导的癌细胞运动性在这里，我们将研究Runx 2精氨酸甲基化的背景下，其典型的作用，成骨细胞分化和骨形成。目的1是表征成骨细胞培养模型中的Runx 2。我们还将比较WT Runx 2与不可甲基化的突变体Runx 2，以及操纵介导Runx 2的甲基转移酶的结果甲基化目的2：探讨Runx 2精氨酸甲基化在调节肿瘤细胞的生理和功能中的作用。与BMP-Smads通路相互作用。最后，目的3是定义Runx 2的精氨酸甲基化，以及Runx 2的精氨酸甲基化。在体内颅骨发育过程中介导Runx 2甲基化的甲基转移酶的表达，比较WT与不可甲基化的Runx 2在颅骨器官培养物中的成骨潜力。总体而言，这一项提案提出了这样一个假设，即精氨酸甲基化是成骨过程中Runx 2活性所必需的。分化和BMP-Smad信号应答所必需的。此外，我们在研究中还纳入了设计基因组和蛋白质组学分析，以促进Runx 2蛋白质-蛋白质的公正发现它们包括Runx 2基因组靶点和受其精氨酸甲基化影响的Runx 2调节基因。从长远来看，我们设想翻译在这个探索性项目中获得的知识，以提高了解骨骼发育，稳态和再生，并提供新的治疗方法解决骨骼疾病的方法。