SMCHD1 pathways as candidate targets for FSHD

描述(由申请人提供)：面部肩关节骨营养不良(FSHD)是由于D4Z4重复的表观遗传抑制减少导致DUX4逆转录基因的表达而引起的。Smchd1基因突变通过其在D4Z4重复序列的直接抑制活性导致D4Z4表观遗传抑制降低，从而导致FSHD。这项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因子(S)的活性的FSHD的治疗方法，该因子在D4Z4重复序列上对抗Smchd1的表观遗传活性。研究设计的具体目标是确定Smchd1活性的正向和负向调节器，以及它们与D4Z4大卫星重复和DUX4表达的表观遗传抑制的上位关系。目的1鉴定调控Smchd1转录后和翻译后生产和活性的途径的分子组成和生物学功能，为Smchd1在FSHD肌肉中的治疗调控提供合理的依据。目的2验证FSHD2相关的Smchd1变异体部分抑制野生型蛋白的活性或稳定性的假设，并为以变异体为靶点作为治疗方法提供理论基础。目的3鉴定Smchd1抑制复合体的成分，并确定它们在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患者D4Z4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.