SMCHD1 pathways as candidate targets for FSHD

描述（由申请方提供）：面肩肱营养不良（FSHD）是由D4Z4重复序列的表观遗传抑制减少引起的，D4Z4重复序列导致DUX4逆转录基因表达。SMCHD1的突变通过其在D4Z4重复序列处的直接阻遏物活性导致D4Z4表观遗传阻遏降低，并导致FSHD。本申请的广泛和长期目标是基于增加SMCHD1活性或蛋白水平，或降低在D4Z4重复处抵消SMCHD1表观遗传活性的因子的活性，开发FSHD的疗法。研究设计的具体目标是确定SMCHD1活性的正调节剂和负调节剂及其与D4Z4宏卫星重复序列和DUX4表达的表观遗传抑制的上位关系。目的1明确SMCHD1转录后和翻译后表达及活性调控通路的分子组成和生物学功能，为SMCHD1在FSHD肌肉中的治疗性调控提供理论依据。目的2将检验FSHD2相关SMCHD1变体部分抑制野生型蛋白的活性或稳定性的假设，并提供靶向变体亚型作为治疗方法的基本原理。目的研究SMCHD1阻遏复合物的3个组分，并确定它们在D4Z4表观遗传阻遏中的作用。总之，这些研究将为基于增加FSHD个体中D4Z4的表观遗传抑制的未来治疗开发提供基础。

DESCRIPTION (provided by applicant): Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 repeat that results in expression of the DUX4 retrogene. Mutations in SMCHD1 result in decreased D4Z4 epigenetic repression through its direct repressor activity at the D4Z4 repeat and cause FSHD. The broad and long-term goal of this application is to develop therapies for FSHD based on increasing SMCHD1 activity or protein level, or decreasing the activity of factor(s) that counter-act SMCHD1 epigenetic activity at the D4Z4 repeats. The specific goal of the research design is to determine the positive and negative modulators of SMCHD1 activity and their epistatic relationship to the epigenetic repression of the D4Z4 macrosatellite repeat and DUX4 expression. Aim 1 will identify the molecular components and the biological functions of the pathways that regulate the post-transcriptional and post-translational production and activity of SMCHD1, and provide a rational basis for the therapeutic modulation of SMCHD1 in FSHD muscle. Aim 2 will test the hypothesis that FSHD2-associated SMCHD1 variants partially inhibit the activity or stability of the wild-type protein and provide a rationale to target the variant isoforms as a therapeutic approach. Aim 3 Identifies components of the SMCHD1 repressive complex and determines their role in D4Z4 epigenetic repression. Together, these studies will provide the basis for future therapeutic development based on increasing the epigenetic repression of D4Z4 in FSHD individuals.