权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of SOX Proteins by Methylation-dependent Proteolysis in Stem Cells and Development

干细胞和发育中甲基化依赖性蛋白水解对 SOX 蛋白的调节

基本信息

批准号：
10531566
负责人：
HUI ZHANG
金额：
$ 30.96万
依托单位：
UNIVERSITY OF NEVADA LAS VEGAS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531566
关键词：
Alleles Animal Model Animals Anophthalmos Binding Biological Process Bladder Brain Cell Cycle Cells Chromatin Cochlea Complex Coupled DNA Methylation DNA Repair DNA Sequence Alteration DNA biosynthesis Defect Development Disease Dose E2F transcription factors Ear Ectoderm Embryo Embryonic Development Endoderm Engineering Epigenetic Process Epithelium Esophagus Eye GLI3 gene Gene Amplification Gene Expression Regulation Genes Genetic Growth HIF1A gene Homeostasis Human Impairment KDM1A gene Learning Disabilities Lysine Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of esophagus Malignant neoplasm of lung Mass Spectrum Analysis Mesoderm Methylation Microphthalmos Motor Skills Mus Mutant Strains Mice Mutation Ovary PIK3CG gene PTEN gene Pathologic Pathway interactions Pattern Phenotype Phosphorylation Phosphotransferases Physiological Play Pluripotent Stem Cells Protein Dynamics Protein Methylation Proteins Proteolysis Proteomics Proto-Oncogene Proteins c-akt Regulation Research Retina Role Seizures Signal Transduction Skin Syndrome TAL1 gene TP53 gene Testis Threonine Tissues Transcriptional Regulation Tumor Suppressor Proteins adult stem cell blastomere structure brain abnormalities brain cell cell type developmental disease embryo cell embryo tissue embryonic stem cell epigenetic regulation fetal stem cell histone methylation induced pluripotent stem cell insight loss of function mutation malignant breast neoplasm methyl group motor learning mutant nervous system disorder neural non-histone protein novel overexpression pluripotency prevent protein degradation self-renewal stem cell function stem cell model stem cells synergism transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary The CRL4 ubiquitin ligase complexes regulate many important biological processes such as DNA replication, DNA repair, transcriptional regulation, and epigenetic inheritance of DNA methylation. We recently found that CRL4 also regulates the self-renewal and pluripotency of embryonic stem cells (ESCs) through important stem cell proteins such as SOX2 (SRY-box2). SOX2 is a dose-dependent master transcriptional factor that plays a key role in regulating the self-renewal and pluripotency or multipotency of ESCs, iPSCs, and many fetal and adult stem cells. In ESCs, an increase of SOX2 promotes development into ectoderm and mesoderm lineages, while loss or reduction of SOX2 induces differentiation into endoderm and trophectoderm lineages. Even at the 4-cell embryonic stage, the heterogeneous binding of SOX2 to target genes determines the first lineage decision. In human, loss-of-function mutations on a single Sox2 allele is sufficient to cause the familial anophthalmia/microphthalmia syndrome associated with seizures, brain abnormalities, slow growth, delayed motor skills and learning disability. Conversely, gene amplification and over-expression of SOX2 are frequently associated with many poorly differentiated cancers including lung, esophagus, brain, and breast cancers. However, it remains unclear how the SOX2 protein level is regulated in various stem/progenitor cells during development and tissue homeostasis. We recently found that the protein stability of SOX2 is regulated by a novel CRL4-based proteolytic mechanism using lysine methylation as a proteolytic trigger in ESCs and other related cells. Genetic mutation of this particular CRL4 function impairs embryonic development. We propose to unravel the function and regulation of this novel and important CRL4-based proteolytic mechanism in regulating self-renewal and pluripotency of ESCs and during embryonic development. Our specific aim 1 is to define the roles of CRL4-based ubiquitin E3 ligases that target the methylated SOX2 protein for degradation. Our specific aim 2 is to determine how the levels of methylated SOX2 proteins are dynamically regulated during the self-renewal of ESCs. In our specific aim 3, we propose to examine how the function of SOX2 is regulated in animal development using specific genetic mutants defective in the methylation- dependent proteolysis pathway. Since SOX2 is central to many stem cells and pathological loss or elevation of SOX2 levels underlies many diseases, our studies should reveal a novel paradigm by which the self-renewal and pluripotency or multipotency of various stem cells are regulated.

项目总结