Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, inherited skeletal myopathy linked to hypomethylation of the D4Z4 macrosatellite at chromosome 4q35. This epigenetic de-repression permits expression of the transcription factor DUX4, which may drive pathology by direct activation of target genes or through inhibition of the homologous transcription factor PAX7. We demonstrated that PAX7 target gene repression is a superior biomarker of FSHD status compared with DUX4 target gene expression. However, despite importance for clinical trials, there remains no transcriptomic biomarker for FSHD progression. A recent study by Wong et al. [Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies. Hum. Mol. Genet., 29, 1030–1043] performed MRI, muscle biopsy transcriptomics and histopathology on a cohort of FSHD patients with 1-year follow-up. No significant changes in any biomarkers were reported over this time period. However, the authors did not consider PAX7 target gene repression as a marker of FSHD progression. Here we demonstrate that PAX7 target gene repression increases in these paired FSHD samples from year 1 to year 2 and is thus a marker of FSHD progression over 1 year. Moreover, we show that three validated DUX4 target gene expression biomarkers are not associated with FSHD progression over 1 year. We further confirm that PAX7 target gene repression associates with clinical correlates of FSHD disease activity, measured by MRI and histopathology. Thus, PAX7 target gene repression is a uniquely sensitive biomarker of FSHD progression and pathology, valid over a 1 year time frame, implicating its use in clinical trials.

中文翻译：

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PAX7 靶基因抑制与超过 1 年的 FSHD 进展和病理相关。

面肩肱型肌营养不良症 (FSHD) 是一种流行的遗传性骨骼肌病，与染色体 4q35.5 上 D4Z4 大卫星的低甲基化有关。这种表观遗传去抑制允许转录因子 DUX4 的表达，这可能通过直接激活靶基因或通过抑制同源转录因子 PAX7 来驱动病理。我们证明，与 DUX4 靶基因表达相比，PAX7 靶基因抑制是 FSHD 状态的优良生物标志物。然而，尽管临床试验很重要，但仍然没有 FSHD 进展的转录组生物标志物。Wong等人最近的一项研究。[FSHD 肌肉活检中 RNA 表达和疾病活动的纵向测量。哼。摩尔。基因., 29, 1030–1043] 对一组 FSHD 患者进行了 MRI、肌肉活检转录组学和组织病理学研究，并进行了 1 年的随访。在这段时间内，没有报告任何生物标志物的显着变化。然而，作者并未将 PAX7 靶基因抑制视为 FSHD 进展的标志。在这里，我们证明 PAX7 靶基因抑制在这些配对 FSHD 样本中从第 1 年到第 2 年增加，因此是 1 年以上 FSHD 进展的标志。此外，我们表明三个经过验证的 DUX4 靶基因表达生物标志物与 FSHD 超过 1 年的进展无关。我们进一步证实 PAX7 靶基因抑制与 FSHD 疾病活动的临床相关性相关，通过 MRI 和组织病理学测量。因此，PAX7 靶基因抑制是 FSHD 进展和病理的独特敏感生物标志物，