PAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle

Christopher R.S. Banerji*, Maryna Panamarova, Husam Hebaishi, Robert B. White, Frédéric Relaix, Simone Severini, Peter S. Zammit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)
159 Downloads (Pure)

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to hypomethylation of D4Z4 repeats on chromosome 4q causing expression of the DUX4 transcription factor. However, DUX4 is difficult to detect in FSHD muscle biopsies and it is debatable how robust changes in DUX4 target gene expression are as an FSHD biomarker. PAX7 is a master regulator of myogenesis that rescues DUX4-mediated apoptosis. Here, we show that suppression of PAX7 target genes is a hallmark of FSHD, and that it is as major a signature of FSHD muscle as DUX4 target gene expression. This is shown using meta-analysis of over six FSHD muscle biopsy gene expression studies, and validated by RNA-sequencing on FSHD patient-derived myoblasts. DUX4 also inhibits PAX7 from activating its transcriptional target genes and vice versa. Furthermore, PAX7 target gene repression can explain oxidative stress sensitivity and epigenetic changes in FSHD. Thus, PAX7 target gene repression is a hallmark of FSHD that should be considered in the investigation of FSHD pathology and therapy.

Original languageEnglish
Article number2152
Pages (from-to)1-13
JournalNature Communications
Volume8
Issue number1
Early online date18 Dec 2017
DOIs
Publication statusPublished - 18 Dec 2017

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