King's College London

Research portal

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

Research output: Contribution to journalReview articlepeer-review

Original languageEnglish
Article numbere13695
JournalEMBO Molecular Medicine
Volume13
Issue number8
DOIs
Accepted/In press2021
Published9 Aug 2021

Bibliographical note

Funding Information: We thank Rabi N. Tawil of the University of Rochester Medical Center, New York, USA, for images used in Fig?2. All study subjects consented to needle muscle biopsy procedures under a study protocol approved by the?Institutional Review Board of the University of Rochester Medical Center, NY, USA. We also thank Giorgio Tasca of the Unit? Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy, for the images in Fig?3, for which the patient consented to having the images shown. We are grateful to Daniel C. L. Zammit for producing Figs?1 and 4. We also thank Michael Kyba, Massimo Ganassi and Philipp Heher for constructive comments on the manuscript. The Zammit laboratory was supported by the Medical Research Council (MR/P023215/1 and MR/S002472/1), FSH Society (FSHS-82013-06, FSHS-82017-05 and FSHDFall2019-05482908070), Muscular Dystrophy UK (19GRO-PG12-0493) and Association Fran?aise contre les Myopathies (AFM 17865). Funding Information: We thank Rabi N. Tawil of the University of Rochester Medical Center, New York, USA, for images used in Fig 2 . All study subjects consented to needle muscle biopsy procedures under a study protocol approved by the Institutional Review Board of the University of Rochester Medical Center, NY, USA. We also thank Giorgio Tasca of the Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy, for the images in Fig 3 , for which the patient consented to having the images shown. We are grateful to Daniel C. L. Zammit for producing Figs 1 and 4 . We also thank Michael Kyba, Massimo Ganassi and Philipp Heher for constructive comments on the manuscript. The Zammit laboratory was supported by the Medical Research Council (MR/P023215/1 and MR/S002472/1), FSH Society (FSHS‐82013‐06, FSHS‐82017‐05 and FSHDFall2019‐05482908070), Muscular Dystrophy UK (19GRO‐PG12‐0493) and Association Française contre les Myopathies (AFM 17865). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454