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PAX7 target gene repression associates with FSHD progression and pathology over 1 year
- Source :
- Human Molecular Genetics. 29:2124-2133
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
Abstract
- 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.
- Subjects :
- Male
musculoskeletal diseases
congenital, hereditary, and neonatal diseases and abnormalities
Pathology
medicine.medical_specialty
Biology
Transcriptome
03 medical and health sciences
0302 clinical medicine
DUX4
Genetics
medicine
Humans
Facioscapulohumeral muscular dystrophy
Epigenetics
Muscle, Skeletal
Molecular Biology
Gene
Psychological repression
Genetics (clinical)
030304 developmental biology
Homeodomain Proteins
0303 health sciences
Sequence Analysis, RNA
Infant
PAX7 Transcription Factor
General Medicine
medicine.disease
Magnetic Resonance Imaging
Muscular Dystrophy, Facioscapulohumeral
Gene Expression Regulation
Child, Preschool
Biomarker (medicine)
Female
Chromosomes, Human, Pair 4
Candidate Disease Gene
Biomarkers
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....fb49805c3390041bf82ffff207858937