Molecular Pathways Regulated By DUX4, an FSHD-Associated Gene

FSHD 相关基因 DUX4 调控的分子通路

基本信息

批准号：
8617227
负责人：
Michael Kyba
金额：
$ 41.07万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-19 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617227
关键词：
Address Affect Alleles Area Binding Biopsy Candidate Disease Gene Cell Culture System Cell model Cells Chromatin Chromosomes, Human, Pair 4 Competitive Binding Consensus Sequence D4Z4 DNA Binding DNA lesion Disease Doxycycline Duchenne muscular dystrophy Elements Enhancers Facioscapulohumeral Muscular Dystrophy Female Flow Cytometry Frequencies Gene Expression Gene Targeting Genes Goals Heterochromatin In Vitro Incidence Individual Limb structure Link Mediating Modeling Molecular Mus Muscle Muscle function Muscle satellite cell Muscular Dystrophies Myoblasts Myopathy Natural regeneration Open Reading Frames Oxidative Stress Pathology Pathway interactions Patients Phenotype Prevalence Proteomics Regulation Regulatory Pathway Repetitive Sequence Repression Resistance Series Site Stem cells Surface System Testing Tissues Toxic effect United States X Chromosome X Inactivation base biceps brachii muscle biological adaptation to stress deltoid muscle effective therapy embryonic stem cell gain of function homeodomain loss of function male mouse genome mouse model muscle regeneration novel overexpression progenitor promoter public health relevance response satellite cell stem telomere transcription factor

项目摘要

DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive muscular dystrophy affecting approximately 1/20,000 individuals. Although the disease is caused by a deletion of repeated sequence on chromosome 4, which is thought to inappropriately activate nearby genes, the identity of the key causative gene is unknown and mechanisms relating genes in the area to muscle pathology are unknown. There is currently no effective treatment for FSHD. We have screened candidate genes from the FSHD region of chromosome 4 in a cell culture system, and identified a gene (the double-homeodomain transcription factor, DUX4, which is embedded within the D4Z4 repeats on chromosome 4) with extreme toxicity to myoblasts. Using an inducible gene expression system, we show that expression of DUX4 causes changes in expression of a set of genes previously identified in microarray and proteomic studies as specifically misregulated in FHSD, including elements of stress response pathways, and the transcription factor MyoD. We further show that these responses involve competition with Pax7, a transcription factor at the apex of the myogenic hierarchy with a highly related homeodomain. We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate novel cell and mouse models for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD (Aim 3).

描述（由申请人提供）：Facioscapulohumeral肌肉营养不良（FSHD）是一种遗传学显着的进行性肌肉营养不良，影响约1/20,000个个体。尽管该疾病是由于4号染色体上重复序列的缺失引起的，该疾病被认为是不当激活附近基因的，但关键原因基因的身份尚不清楚，并且该区域中基因与肌肉病理学的机制尚不清楚。目前没有有效的FSHD治疗方法。我们已经筛选了细胞培养系统中染色体4染色体的FSHD区域的候选基因，并鉴定了一个基因（双域转录因子DUX4，该基因嵌入了D4Z4在4染色体4染色体上的重复序列中），对肌母细胞极度毒性。使用诱导基因表达系统，我们表明DUX4的表达会导致一组先前在微阵列和蛋白质组学研究中鉴定的基因表达的变化，该基因在FHSD中特异性误导，包括应力响应途径的元素以及转录因子MYOD。我们进一步表明，这些响应涉及与PAX7的竞争，Pax7是肌源性层次结构顶端的转录因子，具有高度相关的同源域。 We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate novel cell and mouse models for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD（目标3）。