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Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy

Banerji, CRS; Panamarova, M; Pruller, J; Figeac, N; Hebaishi, H; Fidanis, E; Saxena, A; ... Zammit, PS; + view all (2019) Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy. Human Molecular Genetics 10.1093/hmg/ddy405. (In press). Green open access

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Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic de-repression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time-points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time-points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. Selected for further analysis here, were pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via PGC1α, the co-factor and activator of ERRα. PGC1α knock-down caused hypotrophic myotubes to form from healthy myoblasts. Known ERRα agonists and safe food supplements Biochanin A, Genistein or Daidzein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex-vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily-available food supplements.

Type: Article
Title: Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddy405
Publisher version: https://doi.org/10.1093/hmg/ddy405
Language: English
Additional information: Copyright © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Facioscapulohumeral muscular dystrophy, FSHD, transcriptomics, skeletal muscle, myogenesis, PGC1α, ERRα, Biochanin A, mitochondria, muscular dystrophy, facioscapulohumeral mitochondria myogenesis
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: http://discovery.ucl.ac.uk/id/eprint/10065163
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