Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal-most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain-of-function model is a satisfying “bottom-up” genotype-to-phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this “top-down” finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by “DUX4opathy” models has implications for developing therapies and current clinical trials.

中文翻译：

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面肩肱型肌营养不良症的病理机制和生物标志物：DUX4 和 PAX7 的作用

面肩肱型肌营养不良症 (FSHD) 的特点是进行性骨骼肌无力和萎缩。FSHD 与染色体 4q35 亚端粒 D4Z4 大卫星的表观遗传去抑制有关。表观遗传去抑制允许最远端的 D4Z4 单元转录DUX4，并通过剪接至允许的 4qA 单倍型上的 Poly(A) 信号来稳定转录物。先锋转录因子 DUX4 可激活驱动 FSHD 病理的靶基因。虽然这种毒性功能获得模型是令人满意的“自下而上”基因型与表型联系，但 DUX4 在肌肉中很少检测到，并且 DUX4 靶基因表达在患者中不一致。FSHD 的一个可靠生物标志物是 PAX7（肌生成的主要调节因子）靶基因评分的抑制。然而，尚不清楚这种“自上而下”的发现与 FSHD 和 DUX4 特征的基因组变化有何联系。在这里，我们探讨了 DUX4 和 PAX7 在 FSHD 病理学中的作用和相互作用，以及这两种转录因子之间的关系如何通过免疫系统和肌肉再生加深理解。考虑“DUX4path”模型如何代表 FSHD 病理机制对于开发治疗方法和当前的临床试验具有重要意义。