Molecular Pathways Regulated By DUX4, an FSHD-Associated Gene

FSHD 相关基因 DUX4 调控的分子通路

• 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
• 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

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）：面肩肱型肌营养不良症 (FSHD) 是一种遗传显性的进行性肌营养不良症，影响约 1/20,000 人。尽管这种疾病是由 4 号染色体上重复序列的缺失引起的，人们认为这会不适当地激活附近的基因，但关键致病基因的身份尚不清楚，并且该区域的基因与肌肉病理学的相关机制尚不清楚。目前尚无针对 FSHD 的有效治疗方法。我们在细胞培养系统中筛选了 4 号染色体 FSHD 区域的候选基因，并鉴定了一个对成肌细胞具有极大毒性的基因（双同源域转录因子 DUX4，嵌入在 4 号染色体上的 D4Z4 重复序列中）。使用诱导型基因表达系统，我们发现 DUX4 的表达会导致之前在微阵列和蛋白质组学研究中发现的一组基因表达发生变化，这些基因在 FHSD 中特别失调，包括应激反应途径的元件和转录因子 MyoD。我们进一步表明，这些反应涉及与 Pax7 的竞争，Pax7 是位于肌源层次结构顶端的转录因子，具有高度相关的同源结构域。我们建议研究 DUX4 下游的分子通路，并鉴定与 DUX4 和 Pax7 相反调节的肌肉再生相关基因（目标 1），以基于患者来源的 D4Z4/DUX4 序列的表达生成新的 FSHD 细胞和小鼠模型（目标 2），并检验 FSHD 中肌肉干细胞或祖细胞区室特别受 DUX4 影响的假设（目标 3）。