Himeda Charis L, Jones Takako I, Jones Peter L
The Wellstone Program and the Departments of Cell and Developmental Biology and Neurology, University of Massachusetts Medical School , Worcester, Massachusetts.
Antioxid Redox Signal. 2015 Jun 1;22(16):1463-82. doi: 10.1089/ars.2014.6090. Epub 2014 Dec 4.
Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression.
In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD.
Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets?
Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.
异常的表观遗传调控是许多疾病和复杂病症的一个重要方面。面肩肱型肌营养不良症（FSHD）是一种影响各年龄段个体的进行性肌病，由一个大卫星重复序列的遗传和表观遗传调控紊乱引起。FSHD为研究与疾病相关的表观遗传修饰因子以及调控基因表达的表观遗传调控一般机制提供了一个有力模型。
在一个基因允许的等位基因背景下，FSHD在所有已知病例中一致的一个方面是疾病位点的异常表观遗传状态。此外，染色质调节因子SMCHD1（染色体结构维持铰链域蛋白1）中的某些突变足以导致FSHD2并加重FSHD1的疾病严重程度。因此，有多种途径可产生FSHD所需的表观遗传失调。
为什么一些具有FSHD遗传条件的个体出现疾病病理，而另一些人仍无症状？同样，个体之间的疾病进展差异很大。遗传背景和环境因素在决定FSHD的疾病表现、进展和严重程度方面的相对贡献是什么？调节疾病位点的表观遗传因素之间的相互作用是什么，哪些（如果有的话）是可行的治疗靶点？
表观遗传调控是FSHD一个潜在的有力治疗靶点。确定可预测疾病严重程度的表观遗传特征并识别FSHD中的疾病修饰因子谱对于开发有效疗法至关重要。
