SMCHD1 pathways as candidate targets for FSHD

描述（由申请人提供）：面部肩周骨营养不良症（FSHD）是由D4Z4重复基因的表观遗传抑制减少导致DUX4逆转录基因的表达引起的。SMCHD1突变通过其在D4Z4重复上的直接抑制活性导致D4Z4表观遗传抑制减少，并导致FSHD。该应用的广泛和长期目标是开发基于增加SMCHD1活性或蛋白质水平，或降低在D4Z4重复序列上抑制SMCHD1表观遗传活性的因子活性的FSHD治疗方法。本研究设计的具体目的是确定SMCHD1活性的正、负调节因子及其与D4Z4大卫星重复序列和DUX4表达的表观遗传抑制的关系。目的1将确定调节SMCHD1转录后和翻译后产生和活性的途径的分子成分和生物学功能，为FSHD肌肉中SMCHD1的治疗性调节提供合理依据。目的2将验证fshd2相关SMCHD1变异体部分抑制野生型蛋白活性或稳定性的假设，并为靶向变异体亚型作为治疗方法提供理论依据。目的3鉴定SMCHD1抑制复合体的组分并确定其在D4Z4表观遗传抑制中的作用。总之，这些研究将为未来基于增加FSHD个体中D4Z4的表观遗传抑制的治疗开发提供基础。

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.