SMCHD1 Pathways as Candidate Targets for FSHD

SMCHD1 通路作为 FSHD 的候选目标

• 批准号: 10438685
• 负责人: Stephen J Tapscott
• 金额: $ 15.62万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438685
• 关键词: Affect; Binding; Binding Sites; Cells; Chromatin; Chromatin Structure; Complex; D4Z4; Dependence; Development; Disease; Epigenetic Process; Facioscapulohumeral; Facioscapulohumeral Muscular Dystrophy; Failure; Family; Future; Gene Mutation; Genome; Goals; Health; Human; Intervention; Maintenance; Mediating; Modeling; Modification; Molecular; Molecular Biology; Muscle Cells; Mutation; Pathway interactions; Persons; Post-Translational Protein Processing; Production; Proteins; Regulation; Repetitive Sequence; Repression; Research; Role; Set protein; Skeletal Muscle; Testing; Validation; chromatin modification; epigenetic regulation; induced pluripotent stem cell; prevent; protein complex; recruit; stem cells; therapeutic development; therapy design; therapy development

PROJECT SUMMARY Facioscapulohumeral dystrophy (FSHD) affects ~1/10,000 people and is caused by decreased epigenetic repression of the DUX4 retrogene with subsequent mis-expression of DUX4 in skeletal muscle. As increasing the SMCHD1-mediated epigenetic repression at the D4Z4 locus silences DUX4 in FSHD1 and FSHD2 muscle cells, this application will take a direct molecular biology approach to identify the diversity of SMCHD1 complexes and the role of each component in establishing and maintaining repressive chromatin structure at the D4Z4 and preventing DUX4 expression in skeletal muscle. The broad and long-term goal is to determine the functional components of the SMCHD1 complexes at the D4Z4 locus as a basis for future therapies directed at increasing epigenetic repression. The major hypothesis is that SMCHD1 forms different interactions depending on post- translational modification, chromatin association, and developmental state of the cell, and that understanding the functional roles of the different complexes will provide simple reductionist models for testing candidate interventions. Aim 1 will determine the proteins complexed with SMCHD1 at the D4Z4 locus and their functional significance, chromatin association, and SUMO dependence. Aim 2 will determine the composition of SMCHD1 complexes at autosomal single copy loci in the genome compared to repetitive regions and to subdomains of the D4Z4. Aim 3 will identify the relative roles of SMCHD1 complex components in the establishment and maintenance of epigenetic modifications during stem cell reprogramming and differentiation. Together, these aims will add clarity to the components of SMCHD1 complexes and their functional roles in D4Z4 epigenetic repression, and provide new opportunities to design interventions to suppress DUX4 expression as a treatment for FSHD.

项目摘要 Facioscapulohumeral营养不良（FSHD）影响〜1/10,000人，并由下降引起 DUX4逆转的表观遗传抑制，随后在骨骼中对DUX4的错误表达 肌肉。随着在D4Z4基因座沉默dux4上增加SMCHD1介导的表观遗传抑制 在FSHD1和FSHD2肌肉细胞中，该应用将采用直接的分子生物学方法 确定SMCHD1复合物的多样性以及每个组件在建立和 在D4Z4保持抑制性染色质结构并防止骨骼中的DUX4表达 肌肉。广泛而长期的目标是确定SMCHD1的功能组件 D4Z4基因座的复合物是针对表观遗传学增加的将来疗法的基础 抑制。主要的假设是，SMCHD1取决于后 - 翻译修饰，染色质关联和细胞的发育状态，并且 了解不同复合物的功能作用将为简单的还原主义模型提供 测试候选干预措施。 AIM 1将确定与SMCHD1复合的蛋白质 D4Z4基因座及其功能意义，染色质关联和相扑依赖性。目标2将 确定基因组常染色体单拷贝基因座的SMCHD1复合物的组成 与重复区域和D4Z4的子域相比。 AIM 3将确定 SMCHD1复杂组件在建立和维护表观遗传修饰中 在干细胞重编程和分化过程中。这些目标在一起将使 SMCHD1复合物的组成部分及其在D4Z4表观遗传抑制中的功能作用，并且 提供设计干预措施的新机会，以抑制Dux4表达作为治疗 FSHD。