A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with ‘bursts’ of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis. DOI: http://dx.doi.org/10.7554/eLife.04996.001

[1]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[2]  Stephen J. Tapscott,et al.  DUX4 Binding to Retroelements Creates Promoters That Are Active in FSHD Muscle and Testis , 2013, PLoS genetics.

[3]  John R. Yates,et al.  Identification of Long-Lived Proteins Reveals Exceptional Stability of Essential Cellular Structures , 2013, Cell.

[4]  Emily J. Girard,et al.  Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. , 2013, Genes & development.

[5]  L. Kunkel,et al.  Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. , 2013, Human molecular genetics.

[6]  Laurent Gil,et al.  Ensembl 2013 , 2012, Nucleic Acids Res..

[7]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[8]  Daniel G. Miller,et al.  Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2 , 2012, Nature Genetics.

[9]  Elisa Negroni,et al.  Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: a cellular model for FSHD. , 2012, The American journal of pathology.

[10]  Anders Krogh,et al.  Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns , 2012, Genome Biology.

[11]  L. Maquat,et al.  Regulation of cytoplasmic mRNA decay , 2012, Nature Reviews Genetics.

[12]  L. Maquat,et al.  Regulation of cytoplasmic mRNA decay , 2012, Nature Reviews Genetics.

[13]  J. Silberg,et al.  A transposase strategy for creating libraries of circularly permuted proteins , 2012, Nucleic acids research.

[14]  S. Gringhuis,et al.  Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome , 2012, Nature Immunology.

[15]  Abraham P. Fong,et al.  DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. , 2012, Developmental cell.

[16]  The UniProt Consortium,et al.  Reorganizing the protein space at the Universal Protein Resource (UniProt) , 2011, Nucleic Acids Res..

[17]  S. Wilton,et al.  The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression , 2011, PloS one.

[18]  E. Stone,et al.  RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD. , 2011, Molecular cell.

[19]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[20]  S. Harper,et al.  DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo , 2011, Annals of neurology.

[21]  E. Wang,et al.  Analysis and design of RNA sequencing experiments for identifying isoform regulation , 2010, Nature Methods.

[22]  Daniel G. Miller,et al.  Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene , 2010, PLoS genetics.

[23]  Daniel G. Miller,et al.  A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy , 2010, Science.

[24]  B. Blencowe,et al.  Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay , 2010, Proceedings of the National Academy of Sciences.

[25]  E. Gilboa,et al.  Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay , 2010, Nature.

[26]  E. Wagenmakers,et al.  Bayesian hypothesis testing for psychologists: A tutorial on the Savage–Dickey method , 2010, Cognitive Psychology.

[27]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[28]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[29]  A. Rosa,et al.  The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein , 2007, Neuromuscular Disorders.

[30]  R. Kaufman,et al.  Inhibition of the ubiquitin-proteasome system induces stress granule formation. , 2007, Molecular biology of the cell.

[31]  S. Brenner,et al.  Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements , 2007, Nature.

[32]  Tyson A. Clark,et al.  Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. , 2007, Genes & development.

[33]  S. Morley,et al.  The proteasome inhibitor, MG132, promotes the reprogramming of translation in C2C12 myoblasts and facilitates the association of hsp25 with the eIF4F complex. , 2004, European journal of biochemistry.

[34]  H. Ding,et al.  Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. , 1999, Gene.

[35]  L. Maquat,et al.  Intron function in the nonsense-mediated decay of beta-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. , 1998, RNA.

[36]  I. Nonaka,et al.  Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): Immunocytochemical and genetic analyses , 1995, Muscle & nerve. Supplement.