Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7.
Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7.
复制标题
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。
DOI：
10.15252/emmm.202013695
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发表时间：
2021-08-09
影响因子：
11.1
通讯作者：
Zammit PS
中科院分区：
文献类型：
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作者：
Banerji CRS;Zammit PS
面肩肱型肌营养不良症（FSHD）的特征是进行性骨骼肌无力和消瘦。FSHD与染色体4q35处亚端粒D4Z4大卫星的表观遗传去抑制有关。表观遗传去阻遏允许最远端的D4Z4单元转录DUX4，转录物通过剪接到允许的4qA单倍型上的poly（A）信号而稳定。先锋转录因子DUX4激活被提议驱动FSHD病理的靶基因。虽然这种毒性功能获得模型是一种令人满意的“自下而上”的基因型与表型联系，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的可靠生物标志物是PAX7的靶基因评分的抑制，PAX7是肌生成的主要调节因子。然而，目前尚不清楚这种“自上而下”的发现如何与FSHD和DUX4的基因组变化联系起来。在这里，我们探索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FSHD病理机制如何由“DUX4opathy”模型表示，对开发治疗和当前的临床试验具有意义。在这篇综述中，CRS Banerji和PS Zammit讨论了转录因子DUX4和PAX7在面肩肱型肌营养不良症病理学中的关系。
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. In this review CRS Banerji and PS Zammit discuss the relationship between transcription factors DUX4 and PAX7 in the pathology of facioscapulohumeral muscular dystrophy.