[en] Abstract
Double Homeobox 4 (DUX4) is a potent transcription factor encoded by a retrogene mapped in D4Z4 repeated elements on chromosome 4q35. DUX4 has emerged as pivotal in the pathomechanisms of facioscapulohumeral muscular dystrophy (FSHD), a relatively common hereditary muscle wasting condition, although classified as a rare disease. DUX4 contributes to zygote genome activation before its expression is repressed in most somatic tissues through epigenetic mechanisms, including DNA methylation and chromatin modifications. In FSHD, inappropriate activation of DUX4 expression is driven by a complex interplay of genomic and epigenetic alterations. The ectopic presence of DUX4 in skeletal muscle cells activates genes, viral elements and pathways that are typical of very early embryonic development, disturbing cell function and ultimately contributing to muscle weakness and wasting. This review first traces the history of DUX4, from the FSHD genetic linkage studies in the early 1990s, through to identification and characterization of the DUX4 gene in 1999. We then discuss the seminal studies that showed how and why DUX4 is expressed in FSHD and the effects of this ectopic expression in muscle, notably cellular toxicity. Other pathological roles of DUX4, such as participation in cancer and viral infection, are also highlighted. Maintenance of DUX4 in the genome was explained by discovery of the function of DUX4 in zygotic genome activation to institute the totipotent cells of the embryo. Thus, we encompass the gradual transition of DUX4 over the past 25 years from being considered a pseudogene in “junk DNA” to becoming central to understanding the molecular pathogenesis of FSHD and the primary focus for FSHD therapeutics.
Disciplines :
Biochemistry, biophysics & molecular biology Human health sciences: Multidisciplinary, general & others
Author, co-author :
Belayew, Alexandra ; Université de Mons - UMONS > Faculté de Médecine, Pharmacie et Sciences Biomédicales > Service du Doyen de la Faculté de Médecine, Pharmacie et Sciences Biomédicales
Rosa, Alberto L.
Zammit, Peter S.
Language :
English
Title :
DUX4 at 25: how it emerged from “junk DNA” to become the cause of facioscapulohumeral muscular dystrophy
R550 - Institut des Sciences et Technologies de la Santé
Funders :
Argentina National Research Council Medical Research Council, King's College, London, UK
Commentary :
Article revue sur la recherche de la cause génétique de la FSHD, la découverte du gène DUX4 il y a 25 ans et les progrès réalisés depuis lors dans les études de son activité et des fonctions normales et pathologiques de la protéine qu'il exprime.
Deenen JC, Verbeek AL, Verschuuren JJ, van Engelen BG, Voermans NC. Prevalence and incidence rates of 17 neuromuscular disorders: an updated review of the literature. J Neuromuscul Dis. 2025;22143602241313118
J.K. Mah L. Korngut K.M. Fiest J. Dykeman L.J. Day T. Pringsheim N. Jette A systematic review and Meta-analysis on the epidemiology of the muscular dystrophies Can J Neurol Sci 43 1 163 77 26786644
J. Kools J.C. Deenen A.M. Blokhuis A.L. Verbeek N.C. Voermans B.G. van Engelen The Dutch registry for facioscapulohumeral muscular dystrophy: cohort profile and longitudinal patient reported outcomes Neuromuscul Disord 33 12 964 71 38016873
C.R.S. Banerji P.S. Zammit Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7 EMBO Mol Med 13 8 e13695 34151531 8350899
Padberg GWAM. Facioscapulohumeral disease. Doctoral Thesis, Leiden University 1982, (http://hdl.handle.net/1887/25818).
M. Zatz S.K. Marie A. Cerqueira M. Vainzof R.C. Pavanello M.R. Passos-Bueno The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females Am J Med Genet 77 2 155 61 9605290
R. Tawil D. Storvick T.E. Feasby B. Weiffenbach R.C. Griggs Extreme variability of expression in monozygotic twins with FSH muscular dystrophy Neurology 43 2 345 8 8094896
F.H. Tyler F.E. Stephens Studies in disorders of muscle. II clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family Ann Intern Med 32 4 640 60 15411118
R. Tawil S.M. van der Maarel S.J. Tapscott Facioscapulohumeral dystrophy: the path to consensus on pathophysiology Skelet Muscle 4 12 24940479 4060068
G. Ricci I. Scionti F. Sera M. Govi R. D’Amico I. Frambolli F. Mele M. Filosto L. Vercelli L. Ruggiero et al. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy Brain 136 Pt 11 3408 17 24030947 3808686
C.R.S. Banerji P. Cammish T. Evangelista P.S. Zammit V. Straub C. Marini-Bettolo Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms Neuromuscul Disord 30 4 315 28 32327287
K. Eger B. Jordan S. Habermann S. Zierz Beevor’s sign in facioscapulohumeral muscular dystrophy: an old sign with new implications J Neurol 257 3 436 8 19838767
J.E. Hilbert J.T. Kissel E.A. Luebbe W.B. Martens M.P. McDermott D.B. Sanders R. Tawil C.A. Thornton R.T. Moxley Registry scientific advisory C: if you build a rare disease registry, will they enroll and will they use it? Methods and data from the National registry of myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) Contemp Clin Trials 33 2 302 11 22155025
Eichinger K, Heatwole C, Iyadurai S, King W, Baker L, Heininger S, Bartlett A, Dilek N, Martens WB, McDermott M, et al. Facioscapulohumeral muscular dystrophy functional composite outcome measure. Muscle Nerve. 2018. 10.1002:mus.26088.
K.J. Felice W.A. North S.A. Moore K.D. Mathews FSH dystrophy 4q35 deletion in patients presenting with facial-sparing scapular myopathy Neurology 54 10 1927 31 10822431
G. Ricci P. Cammish G. Siciliano R. Tupler H. Lochmuller T. Evangelista Phenotype May predict the clinical course of facioscapolohumeral muscular dystrophy Muscle Nerve 59 6 711 3 30895627
R.B. Fitzsimons Retinal vascular disease and the pathogenesis of facioscapulohumeral muscular dystrophy. A signalling message from wnt?? Neuromuscul Disord 21 4 263 71 21377364
R. Tawil J.T. Kissel C. Heatwole S. Pandya G. Gronseth M. Benatar D. Guideline Development Implementation Subcommittee of the American Academy of N, Practice Issues Review Panel of the American Association of N M. Electrodiagnostic Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology and the practice issues review panel of the American association of neuromuscular & electrodiagnostic medicine Neurology 85 4 357 64 26215877 4520817
G.P. van Dijk E. van der Kooi A. Behin J. Smeets J. Timmermans S. van der Maarel G. Padberg N. Voermans B. van Engelen High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms Funct Neurol 29 3 159 65 25473735 4264782
R.J. Goselink T.H. Schreuder K. Mul N.C. Voermans M. Pelsma I.J. de Groot N. van Alfen B. Franck T. Theelen R.J. Lemmers et al. Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD) BMC Neurol 16 138 27530735 4988042
A. Nikolic G. Ricci F. Sera E. Bucci M. Govi F. Mele M. Rossi L. Ruggiero L. Vercelli S. Ravaglia et al. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National registry BMJ Open 6 1 e007798 26733561 4716236
R.J. Lemmers P.J. van der Vliet R. Klooster S. Sacconi P. Camano J.G. Dauwerse L. Snider K.R. Straasheijm G.J. van Ommen G.W. Padberg et al. A unifying genetic model for facioscapulohumeral muscular dystrophy Science 329 5999 1650 3 20724583 4677822
J. Gabriëls M.C. Beckers H. Ding A. De Vriese S. Plaisance S.M. van der Maarel G.W. Padberg R.R. Frants J.E. Hewitt D. Collen 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 Gene 236 1 25 32 10433963
V. Kowaljow A. Marcowycz E. Ansseau C.B. Conde S. Sauvage C. Matteotti C. Arias E.D. Corona N.G. Nunez O. Leo et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein Neuromuscul Disord 17 8 611 23 17588759
M. Dixit E. Ansseau A. Tassin S. Winokur R. Shi H. Qian S. Sauvage C. Matteotti A.M. van Acker O. Leo et al. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1 Proc Natl Acad Sci U S A 104 46 18157 62 17984056 2084313
L.V. Gatica A.L. Rosa A complex interplay of genetic and epigenetic events leads to abnormal expression of the DUX4 gene in facioscapulohumeral muscular dystrophy Neuromuscul Disord 26 12 844 52 27816329
M. Richards F. Coppee N. Thomas A. Belayew M. Upadhyaya Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled? Hum Genet 131 3 325 40 21984394
A.E. Campbell A.E. Belleville R. Resnick S.C. Shadle S.J. Tapscott Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle Hum Mol Genet 27 R2 R153 62 29718206 6061842
Meryon E. On granular and fatty degeneration of the voluntary muscles. Med Chir Trans 1852, 35:73–84.
Cruveilhiers J. Mémoire Sur La paralysie musculaire atrophique. Bulletins de l’Académie de Médecine 1852–3, 18:490–502, 546–583.
Duchenne G-BA. Recherches Sur La paralysie musculaire pseudohypertrophique, Ou paralysie myo-sclérosique. Arch Gén Méd 1868, 11:5–25,179–209, 305–321, 421–443, 552–588.
L. Landouzy J. Dejerine De La myopathie atrophique progressive (myopathie hérérlitaire débutant, Dans l’enfance, par La face, Sans altération du système nerveux) Comptes Rendus Hebdomadaires Des Séances De l’Académie Des Sciences 98 53 5
Landouzy L, Dejerine J. De la myopathie atrophique progressive (myopathie sans neuropathie débutant d’ordinaire dans l’enfance par la face. In: Revue de médecine. vol. 5: Felix Alcan; 1885: 253–366.
Y. Sorrel-Dejerine M. Fardeau Birth and metamorphosis of Landouzy-Dejerine progressive atrophic myopathy Rev Neurol (Paris) 138 12 1041 51 6763289
Erb Ueber die ‘‘juvenile form der progressiven muskelatrophie und Ihre beziehungen Zur sogenannten pseudohypertrophie der muskeln Deutsch Archiv Klin Med 34 467 519
Walton JN. Dystrophia Muscularis progressiva. In: Progressive Muskeldystrophie Myotonie · Myasthenie: Symposium vom 30 November bis 4 Dezember 1965 anläßlich der 125 Wiederkehr des Geburtstages von Wilhelm Erb. Kuhn E Springer Berlin Heidelberg; 1966: 57–76.
Erb WH. Dystrophia muscularis progressiva. Klinische und pathologisch-anatomische studien. Dtsch Z Nervenheilkd 1891, 1:13–94.
Calder A. The remarkable origins of FSHD research in America. https://www.fshdsociety.org/2020/11/16/the-remarkable-origins-of-fshd-research-in-america/ 2020.
K.M. Flanigan C.M. Coffeen L. Sexton D. Stauffer S. Brunner M.F. Leppert Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy Neuromuscul Disord 11 6–7 525 9 11525880
E.P. Hoffman R.H. Brown Jr L.M. Kunkel Dystrophin: the protein product of the Duchenne muscular dystrophy locus Cell 51 6 919 28 3319190
P.W. Lunt A workshop on facioscapulohumeral (Landouzy-Dejerine) disease, manchester, 16 to 17 November 1988 J Med Genet 26 8 535 7 2671375 1015680
M. Sarfarazi M. Upadhyaya G. Padberg M. Pericak-Vance T. Siddique G. Lucotte P. Lunt An exclusion map for facioscapulohumeral (Landouzy-Dejerine) disease J Med Genet 26 8 481 4 2769720 1015666
M. Upadhyaya P.W. Lunt M. Sarfarazi W. Broadhead J. Daniels M. Owen P.S. Harper DNA marker applicable to presymptomatic and prenatal diagnosis of facioscapulohumeral disease Lancet 336 8726 1320 1 1978143
C. Wijmenga R.R. Frants O.F. Brouwer P. Moerer J.L. Weber G.W. Padberg Location of facioscapulohumeral muscular dystrophy gene on chromosome 4 Lancet 336 8716 651 3 1975852
C. Wijmenga J.E. Hewitt L.A. Sandkuijl L.N. Clark T.J. Wright H.G. Dauwerse A.M. Gruter M.H. Hofker P. Moerer R. Williamson et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy Nat Genet 2 1 26 30 1363881
C. Wijmenga O.F. Brouwer G.W. Padberg R.R. Frants Transmission of de-novo mutation associated with facioscapulohumeral muscular dystrophy Lancet 340 8825 985 6 1357400
T.J. Wright C. Wijmenga L.N. Clark R.R. Frants R. Williamson J.E. Hewitt Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11 Hum Mol Genet 2 10 1673 8 7903581
C. Wijmenga T.J. Wright M.J. Baan G.W. Padberg R. Williamson G.J. van Ommen J.E. Hewitt M.H. Hofker R.R. Frants Physical mapping and YAC-cloning connects four genetically distinct 4qter loci (D4S163, D4S139, D4F35S1 and D4F104S1) in the FSHD gene-region Hum Mol Genet 2 10 1667 72 8268920
J.C. van Deutekom C. Wijmenga E.A. van Tienhoven A.M. Gruter J.E. Hewitt G.W. Padberg G.J. van Ommen M.H. Hofker R.R. Frants FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit Hum Mol Genet 2 12 2037 42 8111371
Lee JH, Goto K, Matsuda C, Arahata K. Characterization of a tandemly repeated 3.3-kb Kpnl unit in the facioscapulohumeral muscular dystrophy (FSHD) gene region on chromosome 4q35. Muscle Nerve Supplement 1995(2):S6–13.
J.E. Hewitt R. Lyle L.N. Clark E.M. Valleley T.J. Wright C. Wijmenga J.C. van Deutekom F. Francis P.T. Sharpe M. Hofker et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy Hum Mol Genet 3 8 1287 95 7987304
S.T. Winokur U. Bengtsson J. Feddersen K.D. Mathews B. Weiffenbach H. Bailey R.P. Markovich J.C. Murray J.J. Wasmuth M.R. Altherr et al. The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease Chromosome Res 2 3 225 34 8069466
U. Bengtsson M.R. Altherr J.J. Wasmuth S.T. Winokur High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q Hum Mol Genet 3 10 1801 5 7849703
G. Deidda S. Cacurri P. Grisanti E. Vigneti N. Piazzo L. Felicetti Physical mapping evidence for a duplicated region on chromosome 10qter showing high homology with the facioscapulohumeral muscular dystrophy locus on chromosome 4qter Eur J Hum Genetics: EJHG 3 3 155 67 7583041
Bakker E, Wijmenga C, Vossen RH, Padberg GW, Hewitt J, van der Wielen M, Rasmussen K, Frants RR. The FSHD-linked locus D4F104S1 (p13E-11) on 4q35 has a homologue on 10qter. Muscle Nerve Supplement 1995(2):S39–44.
R.J. Lemmers P.J. van der Vliet K.J. van der Gaag S. Zuniga R.R. Frants P. de Knijff S.M. van der Maarel Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution Am J Hum Genet 86 3 364 77 20206332 2833386
M. Rossi E. Ricci L. Colantoni G. Galluzzi R. Frusciante P.A. Tonali L. Felicetti The facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure BMC Med Genet 8 8 17335567 1821008
G. Deidda S. Cacurri N. Piazzo L. Felicetti Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD) J Med Genet 33 5 361 5 8733043 1050602
S.M. van der Maarel G. Deidda R.J. Lemmers E. Bakker M.J. van der Wielen L. Sandkuijl J.E. Hewitt G.W. Padberg R.R. Frants A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD) J Med Genet 36 11 823 8 10544225 1734251
S. Ohno So much junk DNA in our genome Brookhaven Symp Biol 23 366 70 5065367
I. Scionti F. Greco G. Ricci M. Govi P. Arashiro L. Vercelli A. Berardinelli C. Angelini G. Antonini M. Cao et al. Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy Am J Hum Genet 90 4 628 35 22482803 3322229
C. Wijmenga R.R. Frants J.E. Hewitt J.C. van Deutekom M. van Geel T.J. Wright G.W. Padberg M.H. Hofker G.J. van Ommen Molecular genetics of facioscapulohumeral muscular dystrophy Neuromuscul Disord 3 5–6 487 91 8186699
P.W. Lunt P.E. Jardine M.C. Koch J. Maynard M. Osborn M. Williams P.S. Harper M. Upadhyaya Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD) Hum Mol Genet 4 5 951 8 7633457
M. Zatz S.K. Marie M.R. Passos-Bueno M. Vainzof S. Campiotto A. Cerqueira C. Wijmenga G. Padberg R. Frants High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families Am J Hum Genet 56 1 99 105 7825608 1801310
R. Tupler L. Barbierato M. Memmi C.A. Sewry D. De Grandis P. Maraschio L. Tiepolo A. Ferlini Identical de Novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression J Med Genet 35 9 778 83 9733041 1051435
R.C. Griggs R. Tawil M. McDermott J. Forrester D. Figlewicz B. Weiffenbach Monozygotic twins with facioscapulohumeral dystrophy (FSHD): implications for genotype/phenotype correlation. FSH-DY group Muscle Nerve Supplement 2 S50 55 7739626
R. Tupler A. Berardinelli L. Barbierato R. Frants J.E. Hewitt G. Lanzi P. Maraschio L. Tiepolo Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy J Med Genet 33 5 366 70 8733044 1050603
J.C. van Deutekom E. Bakker R.J. Lemmers M.J. van der Wielen E. Bik M.H. Hofker G.W. Padberg R.R. Frants Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1 Hum Mol Genet 5 12 1997 2003 8968754
J.S. Thompson L.M. Johnson M. Grunstein Specific repression of the yeast silent mating locus HMR by an adjacent telomere Mol Cell Biol 14 1 446 55 8264612 358394
A. Hecht S. Strahl-Bolsinger M. Grunstein Spreading of transcriptional repressor SIR3 from telomeric heterochromatin Nature 383 6595 92 6 8779721
G. Stadler F. Rahimov O.D. King J.C. Chen J.D. Robin K.R. Wagner J.W. Shay C.P. Emerson Jr W.E. Wright Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy Nat Struct Mol Biol 20 6 671 8 23644600 3711615
R.J. Lemmers P. de Kievit L. Sandkuijl G.W. Padberg G.J. van Ommen R.R. Frants S.M. van der Maarel Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere Nat Genet 32 2 235 6 12355084
M. van Geel M.C. Dickson A.F. Beck D.J. Bolland R.R. Frants S.M. van der Maarel P.J. de Jong J.E. Hewitt Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin Genomics 79 2 210 7 11829491
D. Gabellini M.R. Green R. Tupler Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle Cell 110 3 339 48 12176321
P.G. van Overveld R.J. Lemmers L.A. Sandkuijl L. Enthoven S.T. Winokur F. Bakels G.W. Padberg G.J. van Ommen R.R. Frants S.M. van der Maarel Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy Nat Genet 35 4 315 7 14634647
P.G. van Overveld L. Enthoven E. Ricci M. Rossi L. Felicetti M. Jeanpierre S.T. Winokur R.R. Frants G.W. Padberg S.M. van der Maarel Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy Ann Neurol 58 4 569 76 16178028
J.C. de Greef R.J. Lemmers B.G. van Engelen S. Sacconi S.L. Venance R.R. Frants R. Tawil S.M. van der Maarel Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD Hum Mutat 30 10 1449 59 19728363
W. Zeng J.C. de Greef Y.Y. Chen R. Chien X. Kong H.C. Gregson S.T. Winokur A. Pyle K.D. Robertson J.A. Schmiesing et al. Specific loss of histone H3 lysine 9 trimethylation and HP1gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD) PLoS Genet 5 7 e1000559 19593370 2700282
D.S. Cabianca V. Casa B. Bodega A. Xynos E. Ginelli Y. Tanaka D. Gabellini A long NcRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy Cell 149 4 819 31 22541069 3350859
C.L. Himeda C. Debarnot S. Homma M.L. Beermann J.B. Miller P.L. Jones T.I. Jones Myogenic enhancers regulate expression of the facioscapulohumeral muscular Dystrophy-Associated DUX4 gene Mol Cell Biol 34 11 1942 55 24636994 4019064
E. Mocciaro R. Giambruno S. Micheloni F.M. Cernilogar A. Andolfo C. Consonni M. Pannese G. Ferri V. Runfola G. Schotta et al. WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy Nucleic Acids Res 51 10 5144 61 37021550 10250208
E.J. Grow B.D. Weaver C.M. Smith J. Guo P. Stein S.C. Shadle P.G. Hendrickson N.E. Johnson R.J. Butterfield R. Menafra et al. p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models Nat Genet 53 8 1207 20 34267371 8513633
A. Fox J. Oliva R. Vangipurapu F.M. Sverdrup SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy Skelet Muscle 14 1 30 39627769 11613756
T.I. Jones O.D. King C.L. Himeda S. Homma J.C. Chen M.L. Beermann C. Yan C.P. Emerson Jr J.B. Miller K.R. Wagner et al. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy Clin Epigenetics 7 37 25904990 4405830
Gould T, Jones TI, Jones PL. Precise epigenetic analysis using targeted bisulfite genomic sequencing distinguishes FSHD1, FSHD2, and healthy subjects. Diagnostics (Basel) 2021, 11(8):1469.
H. Ding M.C. Beckers S. Plaisance P. Marynen D. Collen A. Belayew Characterization of a double homeodomain protein (DUX1) encoded by a cDNA homologous to 3.3 kb dispersed repeated elements Hum Mol Genet 7 11 1681 94 9736770
K. Tsumagari L. Qi K. Jackson C. Shao M. Lacey J. Sowden R. Tawil V. Vedanarayanan M. Ehrlich Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers Nucleic Acids Res 36 7 2196 207 18281700 2367708
L. Ciszewski N. Lu-Nguyen A. Slater A. Brennan H.E.L. Williams G. Dickson M.S. Searle L. Popplewell G-quadruplex ligands mediate downregulation of DUX4 expression Nucleic Acids Res 48 8 4179 94 32182342 7192601
G. Bai T. Endres U. Kuhbacher V. Mengoli B.H. Greer E.M. Peacock M.D. Newton T. Stanage M.R. Dello Stritto R. Lungu et al. HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability Mol Cell 84 16 3044 e30603011 39142279 11366124
X.Y. Zhang P.T. Loflin C.W. Gehrke P.A. Andrews M. Ehrlich Hypermethylation of human DNA sequences in embryonal carcinoma cells and somatic tissues but not in sperm Nucleic Acids Res 15 22 9429 49 2825135 306478
L.N. Geng Z. Yao L. Snider A.P. Fong J.N. Cech J.M. Young S.M. van der Maarel W.L. Ruzzo R.C. Gentleman R. Tawil et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy Dev Cell 22 1 38 51 22209328
M. Beckers J. Gabriels S. van der Maarel A. De Vriese R.R. Frants D. Collen A. Belayew Active genes in junk DNA? Characterization of DUX genes embedded within 3.3 kb repeated elements Gene 264 1 51 7 11245978
R. Lyle T.J. Wright L.N. Clark J.E. Hewitt The FSHD-associated repeat, D4Z4, is a member of a dispersed family of homeobox-containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes Genomics 28 3 389 97 7490072
S.T. Winokur U. Bengtsson J.C. Vargas J.J. Wasmuth M.R. Altherr B. Weiffenbach S.J. Jacobsen The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region Hum Mol Genet 5 10 1567 75 8894690
R. Tupler D. Gabellini Molecular basis of facioscapulohumeral muscular dystrophy Cell Mol Life Sci 61 5 557 66 15004695 11138944
J.R. Girton K.M. Johansen Chromatin structure and the regulation of gene expression: the lessons of PEV in Drosophila Adv Genet 61 1 43 18282501
K. Li C.K. Warner J.A. Hodge S. Minoshima J. Kudoh R. Fukuyama M. Maekawa Y. Shimizu N. Shimizu D.C. Wallace A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed J Biol Chem 264 24 13998 4004 2547778
C. Wijmenga S.T. Winokur G.W. Padberg M.I. Skraastad M.R. Altherr J.J. Wasmuth J.C. Murray M.H. Hofker R.R. Frants The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus Hum Genet 92 2 198 203 8103757
J.C. van Deutekom R.J. Lemmers P.K. Grewal M. van Geel S. Romberg H.G. Dauwerse T.J. Wright G.W. Padberg M.H. Hofker J.E. Hewitt et al. Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35 Hum Mol Genet 5 5 581 90 8733123
M. van Geel J.C. van Deutekom A. van Staalduinen R.J. Lemmers M.C. Dickson M.H. Hofker G.W. Padberg J.E. Hewitt P.J. de Jong R.R. Frants Identification of a novel beta-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35 Cytogenet Cell Genet 88 3–4 316 21 10828619
S.T. Winokur Y.W. Chen P.S. Masny J.H. Martin J.T. Ehmsen S.J. Tapscott S.M. van der Maarel Y. Hayashi K.M. Flanigan Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation Hum Mol Genet 12 22 2895 907 14519683
D. Bosnakovski S. Lamb T. Simsek Z. Xu A. Belayew R. Perlingeiro M. Kyba DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation Exp Neurol 214 1 87 96 18723017
E. Ansseau D. Laoudj-Chenivesse A. Marcowycz A. Tassin C. Vanderplanck S. Sauvage M. Barro I. Mahieu A. Leroy I. Leclercq et al. DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation PLoS ONE 4 10 e7482 19829708 2759506
P. Knopp Y.D. Krom C.R. Banerji M. Panamarova L.A. Moyle B. den Hamer S.M. van der Maarel P.S. Zammit DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis J Cell Sci 129 20 3816 31 27744317 5087662
N. Caruso B. Herberth M. Bartoli F. Puppo J. Dumonceaux A. Zimmermann S. Denadai M. Lebosse S. Roche L. Geng et al. Deregulation of the Protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy PLoS Genet 9 6 e1003550 23785297 3681729
D.J. Yip D.J. Picketts Increasing D4Z4 repeat copy number compromises C2C12 myoblast differentiation FEBS Lett 537 1–3 133 8 12606045
C. Arias C.B. Conde A.L. Rosa Cellular toxicity of DUX4, a protein encoded at the fascioscapulo- humeral muscular dystrophy locus FSHD- 1A, depends on nuclear localization Neuromuscul Disord 15 9 709
M. Kawamura-Saito Y. Yamazaki K. Kaneko N. Kawaguchi H. Kanda H. Mukai T. Gotoh T. Motoi M. Fukayama H. Aburatani et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation Hum Mol Genet 15 13 2125 37 16717057
Coppee F, Matteotti C, Ansseau E, Sauvage S, Leclercq I, Leroy A, Marcowycz A, gerbaux D, Figlewicz D, Ding H et al. The DUX gene family and FSHD. In: FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology. Edited by Upadhyaya M, Cooper DN: Taylor & Francis LTD; 2004.
J. Clapp L.M. Mitchell D.J. Bolland J. Fantes A.E. Corcoran P.J. Scotting J.A. Armour J.E. Hewitt Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy Am J Hum Genet 81 2 264 79 17668377 1950813
L. Snider A. Asawachaicharn A.E. Tyler L.N. Geng L.M. Petek L. Maves D.G. Miller R.J. Lemmers S.T. Winokur R. Tawil et al. RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy Hum Mol Genet 18 13 2414 30 19359275 2694690
R.D. Wuebbles S.W. Long M.L. Hanel P.L. Jones Testing the effects of FSHD candidate gene expression in vertebrate muscle development Int J Clin Exp Pathol 3 4 386 400 20490329 2872745
T.I. Jones M. Parilla P.L. Jones Transgenic Drosophila for investigating DUX4 and FRG1, two genes associated with facioscapulohumeral muscular dystrophy (FSHD) PLoS ONE 11 3 e0150938 26942723 4778869
R.D. Palmiter R.L. Brinster R.E. Hammer M.E. Trumbauer M.G. Rosenfeld N.C. Birnberg R.M. Evans Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes Nature 300 5893 611 5 6958982 4881848
D. Garrick S. Fiering D.I. Martin E. Whitelaw Repeat-induced gene Silencing in mammals Nat Genet 18 1 56 9 9425901
L.N. Geng A.E. Tyler S.J. Tapscott Immunodetection of human double homeobox 4 Hybrid (Larchmt) 30 2 125 30
A. Tassin D. Laoudj-Chenivesse C. Vanderplanck M. Barro S. Charron E. Ansseau Y.W. Chen J. Mercier F. Coppee A. Belayew DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy? J Cell Mol Med 17 1 76 89 23206257
M.L. Beermann S. Homma J.B. Miller Proximity ligation assay to detect DUX4 protein in FSHD1 muscle: a pilot study BMC Res Notes 15 1 163 35538497 9092897
C. Claus M. Slavin E. Ansseau C. Lancelot K. Bah S. Lassche M. Fievet A. Greco S. Tomaiuolo A. Tassin et al. The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins Skelet Muscle 13 1 5 36882853 9990282
R.N. Knox J.O. Eidahl L.M. Wallace S.G. Choudury A. Rashnonejad K. Daman M.J. Guggenbiller N.Y. Saad M.E. Hoover L. Zhang et al. Post-Translational modifications of the DUX4 protein impact toxic function in FSHD cell models Ann Neurol 94 2 398 413 37186119 10777487
A.J. Gruber R. Schmidt A.R. Gruber G. Martin S. Ghosh M. Belmadani W. Keller M. Zavolan A comprehensive analysis of 3’ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation Genome Res 26 8 1145 59 27382025 4971764
R.J. Osborne S. Welle S.L. Venance C.A. Thornton R. Tawil Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy Neurology 68 8 569 77 17151338
V. Alexiadis M.E. Ballestas C. Sanchez S. Winokur V. Vedanarayanan M. Warren M. Ehrlich RNAPol-ChIP analysis of transcription from FSHD-linked tandem repeats and satellite DNA Biochim Biophys Acta 1769 1 29 40 17239456
R. Tupler G. Perini M.A. Pellegrino M.R. Green Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy Proc Natl Acad Sci U S A 96 22 12650 4 10535977 23032
T.Q. Tran C. Kioussi Pitx genes in development and disease Cell Mol Life Sci 78 11 4921 38 33844046 11073205
P. Dmitriev M. Lipinski Y.S. Vassetzky Pearls in the junk: dissecting the molecular pathogenesis of facioscapulohumeral muscular dystrophy Neuromuscul Disord 19 1 17 20 18974002
D. Bosnakovski Z. Xu E.J. Gang C.L. Galindo M. Liu T. Simsek H.R. Garner S. Agha-Mohammadi A. Tassin F. Coppee et al. An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies Embo J 27 20 2766 79 18833193 2572182
S.T. Winokur K. Barrett J.H. Martin J.R. Forrester M. Simon R. Tawil S.A. Chung P.S. Masny D.A. Figlewicz Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress Neuromuscul Disord 13 4 322 33 12868502
D. Laoudj-Chenivesse G. Carnac C. Bisbal G. Hugon S. Bouillot C. Desnuelle Y. Vassetzky A. Fernandez Increased levels of adenine nucleotide translocator 1 protein and response to oxidative stress are early events in facioscapulohumeral muscular dystrophy muscle J Mol Med (Berl) 83 3 216 24 15551024
F. Relaix P.S. Zammit Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage Development 139 16 2845 56 22833472
C.R.S. Banerji M. Panamarova H. Hebaishi R.B. White F. Relaix S. Severini P.S. Zammit PAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle Nat Commun 8 1 2152 29255294 5735185
S.H. Choi M.D. Gearhart Z. Cui D. Bosnakovski M. Kim N. Schennum M. Kyba DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes Nucleic Acids Res 44 11 5161 73 26951377 4914088
S. Jagannathan S.C. Shadle R. Resnick L. Snider R.N. Tawil S.M. van der Maarel R.K. Bradley S.J. Tapscott Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells Hum Mol Genet 25 20 4419 31 28171552 6078597
Lemmers R, van der Vliet PJ, Blatnik A, Balog J, Zidar J, Henderson D, Goselink R, Tapscott SJ, Voermans NC, Tawil R et al. Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene. J Med Genet 2022;59(2):180–8.
Y. Ma A. Schwager Karpukhina C. Dib C. Gautier O. Hermine E. Allemand Y.S. Vassetzky Exchange of subtelomeric regions between chromosomes 4q and 10q reverts the FSHD genotype and phenotype Sci Adv 10 18 eadl1922 38691604 11062572
R.J. Lemmers R. Tawil L.M. Petek J. Balog G.J. Block G.W. Santen A.M. Amell P.J. van der Vliet R. Almomani K.R. Straasheijm et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2 Nat Genet 44 12 1370 4 23143600 3671095
S. Mitsuhashi S.E. Boyden E.A. Estrella T.I. Jones F. Rahimov T.W. Yu B.T. Darras A.A. Amato R.D. Folkerth P.L. Jones et al. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2 Neuromuscul Disord 23 12 975 80 24128691
M.E. Blewitt N.K. Vickaryous S.J. Hemley A. Ashe T.J. Bruxner J.I. Preis R. Arkell E. Whitelaw An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse Proc Natl Acad Sci U S A 102 21 7629 34 15890782 1140414
S. Sacconi R.J. Lemmers J. Balog P.J. van der Vliet P. Lahaut M.P. van Nieuwenhuizen K.R. Straasheijm R.D. Debipersad M. Vos-Versteeg L. Salviati et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1 Am J Hum Genet 93 4 744 51 24075187 3791262
R. Cascella C. Strafella V. Caputo R.M. Galota V. Errichiello M. Scutifero R. Petillo G.L. Marella M. Arcangeli L. Colantoni et al. Digenic inheritance of shortened repeat units of the D4Z4 region and a Loss-of-Function variant in SMCHD1 in a family with FSHD Front Neurol 9 1027 30546343 6279899
Huang Z, Yu J, Cui W, Johnson BK, Kim K, Pfeifer GP. The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins. Sci Adv 2021, 7(4):eabb9149.
M.M. Wong S. Hachmer E. Gardner V. Runfola E. Arezza L.A. Megeney C.P. Emerson Jr D. Gabellini F.J. Dilworth SMCHD1 activates the expression of genes required for the expansion of human myoblasts Nucleic Acids Res 52 16 9450 62 38994563 11381350
Balog J, Thijssen PE, Shadle S, Straasheijm KR, van der Vliet PJ, Krom YD, van den Boogaard ML, de Jong A, RJ FL, Tawil R et al. Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 2015, 10(12):1133–1142.
M.L. van den Boogaard R.J. Lemmers J. Balog M. Wohlgemuth M. Auranen S. Mitsuhashi P.J. van der Vliet K.R. Straasheijm R.F. van den Akker M. Kriek et al. Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy Am J Hum Genet 98 5 1020 9 27153398 4863565
K. Hamanaka D. Sikrova S. Mitsuhashi H. Masuda Y. Sekiguchi A. Sugiyama K. Shibuya R. Lemmers R. Goossens M. Ogawa et al. Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy Neurology 94 23 e2441 7 32467133 7455367
C. Strafella V. Caputo S. Bortolani E. Torchia D. Megalizzi G. Trastulli M. Monforte L. Colantoni C. Caltagirone E. Ricci et al. Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD Front Genet 14 1235589 37674478 10477786
C. Ostlund R.M. Garcia-Carrasquillo A. Belayew H.J. Worman Intracellular trafficking and dynamics of double homeodomain proteins Biochemistry 44 7 2378 84 15709750
L.M. Wallace S.E. Garwick W. Mei A. Belayew F. Coppee K.J. Ladner D. Guttridge J. Yang S.Q. Harper DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo Ann Neurol 69 3 540 52 21446026 4098764
E.D. Corona D. Jacquelin L. Gatica A.L. Rosa Multiple protein domains contribute to nuclear import and cell toxicity of DUX4, a candidate pathogenic protein for facioscapulohumeral muscular dystrophy PLoS ONE 8 10 e75614 24116060 3792938
D. Bosnakovski E.A. Toso L.M. Hartweck A. Magli H.A. Lee E.R. Thompson A. Dandapat R.C.R. Perlingeiro M. Kyba The DUX4 homeodomains mediate Inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain J Cell Sci 130 21 3685 97 28935672 5702055
Y. Zhang J.K. Lee E.A. Toso J.S. Lee S.H. Choi M. Slattery H. Aihara M. Kyba DNA-binding sequence specificity of DUX4 Skelet Muscle 6 8 26823969 4730607
J.K. Lee D. Bosnakovski E.A. Toso T. Dinh S. Banerjee T.E. Bohl K. Shi K. Orellana M. Kyba H. Aihara Crystal structure of the double homeodomain of DUX4 in complex with DNA Cell Rep 25 11 2955 e29622953 30540931 6463520
H. Mitsuhashi S. Ishimaru S. Homma B. Yu Y. Honma M.L. Beermann J.B. Miller Functional domains of the FSHD-associated DUX4 protein Biol Open 7 4 bio033977 29618456 5936065
D. Bosnakovski M.T. da Silva S.T. Sunny E.T. Ener E.A. Toso C. Yuan Z. Cui M.A. Walters A. Jadhav M. Kyba A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death Sci Adv 5 9 eaaw7781 31535023 6739093
S. Vuoristo S. Bhagat C. Hyden-Granskog M. Yoshihara L. Gawriyski E.M. Jouhilahti V. Ranga M. Tamirat M. Huhtala I. Kirjanov et al. DUX4 is a multifunctional factor priming human embryonic genome activation iScience 25 4 104137 35402882 8990217
A. Leidenroth J.E. Hewitt A family history of DUX4: phylogenetic analysis of DUXA, B, C and duxbl reveals the ancestral DUX gene BMC Evol Biol 10 364 21110847 3004920
J. Quintero N.Y. Saad S.M. Pagnoni D.K. Jacquelin L.V. Gatica S.Q. Harper A.L. Rosa The DUX4 protein is a co-repressor of the progesterone and glucocorticoid nuclear receptors FEBS Lett 596 20 2644 58 35662006
E. Ansseau J.O. Eidahl C. Lancelot A. Tassin C. Matteotti C. Yip J. Liu B. Leroy C. Hubeau C. Gerbaux et al. Homologous transcription factors DUX4 and DUX4c associate with cytoplasmic proteins during muscle differentiation PLoS ONE 11 1 e0146893 26816005 4729438
A.M. DeSimone J. Leszyk K. Wagner C.P. Emerson Jr Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy Sci Adv 5 12 eaaw7099 31844661 6905861
A.M. Rickard L.M. Petek D.G. Miller Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways Hum Mol Genet 24 20 5901 14 26246499 4581613
Jagannathan S, Ogata Y, Gafken PR, Tapscott SJ, Bradley RK. Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy. eLife 2019, 8:e41740.
Q. Feng L. Snider S. Jagannathan R. Tawil S.M. van der Maarel S.J. Tapscott R.K. Bradley A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy eLife 4 e04996 25564732 4383350
C.R. Banerji P. Knopp L.A. Moyle S. Severini R.W. Orrell A.E. Teschendorff P.S. Zammit beta-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy J R Soc Interface 12 102 20140797 25551153 4277075
M. Ganassi N. Figeac M. Reynaud H.P. Ortuste Quiroga P.S. Zammit Antagonism between DUX4 and DUX4c highlights a pathomechanism operating through beta-Catenin in facioscapulohumeral muscular dystrophy Front Cell Dev Biology 10 802573
Ansseau E, Nachtegael C, Pieters K, Vanderplanck C, Geens M, Sermon K, Wilton SD, Coppee F, Lagneaux L et al. The Role of D4Z4-Encoded Proteins in the Osteogenic Differentiation of Mesenchymal Stromal Cells Isolated from Bone Marrow. Stem Cells Dev 2015, 24(22):2674–86.
J.M. Young J.L. Whiddon Z. Yao B. Kasinathan L. Snider L.N. Geng J. Balog R. Tawil S.M. van der Maarel S.J. Tapscott DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis PLoS Genet 9 11 e1003947 24278031 3836709
Z. Yao L. Snider J. Balog R.J. Lemmers S.M. Van Der Maarel R. Tawil S.J. Tapscott DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle Hum Mol Genet 23 20 5342 52 24861551 4168822
V. Sharma N. Harafuji A. Belayew Y.W. Chen DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells PLoS ONE 8 5 e64691 23717650 3661531
L. Snider L.N. Geng R.J. Lemmers M. Kyba C.B. Ware A.M. Nelson R. Tawil G.N. Filippova S.M. van der Maarel S.J. Tapscott et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene PLoS Genet 6 10 e1001181 21060811 2965761
F. Rahimov O.D. King D.G. Leung G.M. Bibat C.P. Emerson Jr L.M. Kunkel K.R. Wagner Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers Proc Natl Acad Sci U S A 109 40 16234 9 22988124 3479603
G. Tasca M. Pescatori M. Monforte M. Mirabella E. Iannaccone R. Frusciante T. Cubeddu F. Laschena P. Ottaviani E. Ricci Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles PLoS ONE 7 6 e38779 22719944 3374833
N. Broucqsault J. Morere M.C. Gaillard J. Dumonceaux J. Torrents E. Salort-Campana A. Maues De Paula M. Bartoli C. Fernandez A.L. Chesnais et al. Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy Hum Mol Genet 22 20 4206 14 23777630
M. Ferreboeuf V. Mariot B. Bessieres A. Vasiljevic T. Attie-Bitach S. Collardeau J. Morere S. Roche F. Magdinier J. Robin-Ducellier et al. DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles Hum Mol Genet 23 1 171 81 23966205
C.R.S. Banerji P.S. Zammit PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level Hum Mol Genet 28 13 2224 36 31067297 6586142
C.R.S. Banerji PAX7 target gene repression associates with FSHD progression and pathology over 1 year Hum Mol Genet 29 13 2124 33 32347924
C.J. Wong L.H. Wang S.D. Friedman D. Shaw A.E. Campbell C.B. Budech L.M. Lewis R. Lemmers J.M. Statland S.M. van der Maarel et al. Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies Hum Mol Genet 29 6 1030 43 32083293 7158378
C. Vanderplanck E. Ansseau S. Charron N. Stricwant A. Tassin D. Laoudj-Chenivesse S.D. Wilton F. Coppee A. Belayew The FSHD atrophic myotube phenotype is caused by DUX4 expression PLoS ONE 6 10 e26820 22053214 3203905
D. Bosnakovski M.D. Gearhart E.A. Toso O.O. Recht A. Cucak A.K. Jain M.C. Barton M. Kyba p53-independent DUX4 pathology in cell and animal models of facioscapulohumeral muscular dystrophy Dis Models Mech 10 10 1211 6
S.C. Shadle J.W. Zhong A.E. Campbell M.L. Conerly S. Jagannathan C.J. Wong T.D. Morello S.M. van der Maarel S.J. Tapscott DUX4-induced DsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy PLoS Genet 13 3 e1006658 28273136 5362247
P. Dmitriev Y. Bou Saada C. Dib E. Ansseau A. Barat A. Hamade P. Dessen T. Robert V. Lazar R.A. Louzada et al. DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients Free Radic Biol Med 99 244 58 27519269
S.C. Shadle S.R. Bennett C.J. Wong N.A. Karreman A.E. Campbell S.M. van der Maarel B.L. Bass S.J. Tapscott DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD Hum Mol Genet 28 23 3997 4011 31630170 7342170
M. Sasaki-Honda T. Jonouchi M. Arai A. Hotta S. Mitsuhashi I. Nishino R. Matsuda H. Sakurai A patient-derived iPSC model revealed oxidative stress increases facioscapulohumeral muscular dystrophy-causative DUX4 Hum Mol Genet 27 23 4024 35 30107443 6240734
A. Turki M. Hayot G. Carnac F. Pillard E. Passerieux S. Bommart E. Raynaud de Mauverger G. Hugon J. Pincemail S. Pietri et al. Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction Free Radic Biol Med 53 5 1068 79 22796148
P. Heher M. Ganassi A. Weidinger E.N. Engquist J. Pruller T.H. Nguyen A. Tassin A.E. Decleves K. Mamchaoui C.R.S. Banerji et al. Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: metabolic stress as potential therapeutic target Redox Biol 51 102251 35248827 8899416
S. Arbogast H. Kotzur C. Frank N. Compagnone T. Sutra F. Pillard S. Pietri N. Hmada D.M.A. Moussa J. Bride et al. ANT1 overexpression models: some similarities with facioscapulohumeral muscular dystrophy Redox Biol 56 102450 36030628 9434167
A. Karpukhina I. Galkin Y. Ma C. Dib R. Zinovkin O. Pletjushkina B. Chernyak E. Popova Y. Vassetzky Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy Redox Biol 43 102008 34030118 8163973
M. Barro G. Carnac S. Flavier J. Mercier Y. Vassetzky D. Laoudj-Chenivesse Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects J Cell Mol Med 14 1–2 275 89 18505476
C.R.S. Banerji M. Panamarova J. Pruller N. Figeac H. Hebaishi E. Fidanis A. Saxena J. Contet S. Sacconi S. Severini et al. Dynamic transcriptomic analysis reveals suppression of PGC1alpha/ERRalpha drives perturbed myogenesis in facioscapulohumeral muscular dystrophy Hum Mol Genet 28 8 1244 59 30462217
D. Bosnakovski M.D. Gearhart E.A. Toso E.T. Ener S.H. Choi M. Kyba Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression Sci Rep 8 1 16957 30446688 6240038
Lim KRQ, Nguyen Q, Yokota T. DUX4 signalling in the pathogenesis of facioscapulohumeral muscular dystrophy. Int J Mol Sci. 2020;21(3):729.
Mocciaro E, Runfola V, Ghezzi P, Pannese M, Gabellini D. DUX4 role in normal physiology and in FSHD muscular dystrophy. Cells. 2021;10(12):3322.
A. Leidenroth L. Clapp L.M. Mitchell D. Coneyworth F.L. Dearden L. Iannuzzi J.E. Hewitt Evolution of DUX gene macrosatellites in placental mammals Chromosoma 121 5 489 97 22903800
A.M. DeSimone J. Cohen M. Lek A. Lek Cellular and animal models for facioscapulohumeral muscular dystrophy Dis Models Mech 13 10 dmm046904
Y.D. Krom P.E. Thijssen J.M. Young B. den Hamer J. Balog Z. Yao L. Maves L. Snider P. Knopp P.S. Zammit et al. Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a Transgenic mouse model for FSHD PLoS Genet 9 4 e1003415 23593020 3616921
H. Mitsuhashi S. Mitsuhashi T. Lynn-Jones G. Kawahara L.M. Kunkel Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy Hum Mol Genet 22 3 568 77 23108159
A. Pakula A. Lek J. Widrick H. Mitsuhashi K.M. Bugda Gwilt V.A. Gupta F. Rahimov J. Criscione Y. Zhang D. Gibbs et al. Transgenic zebrafish model of DUX4 misexpression reveals a developmental role in FSHD pathogenesis Hum Mol Genet 28 2 320 31 30307508
S.Q. Xie B.J. Leeke C. Whilding R.T. Wagner F. Garcia-Llagostera Y. Low P. Chammas N.T. Cheung D. Dormann M.T. McManus et al. Nucleolar-based dux repression is essential for embryonic two-cell stage exit Genes Dev 36 5–6 331 47 35273077 8973846
A. Dandapat D. Bosnakovski L.M. Hartweck R.W. Arpke K.A. Baltgalvis D. Vang J. Baik R. Darabi R.C. Perlingeiro F.K. Hamra et al. Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene Cell Rep 8 5 1484 96 25176645 4188423
A. Dandapat B.J. Perrin C. Cabelka M. Razzoli J.M. Ervasti A. Bartolomucci D.A. Lowe M. Kyba High frequency hearing loss and hyperactivity in DUX4 Transgenic mice PLoS ONE 11 3 e0151467 26978271 4792399
D. Bosnakovski S.S.K. Chan O.O. Recht L.M. Hartweck C.J. Gustafson L.L. Athman D.A. Lowe M. Kyba Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model Nat Commun 8 1 550 28916757 5601940
D. Bosnakovski A.S. Shams C. Yuan M.T. da Silva E.T. Ener C.W. Baumann A.J. Lindsay M. Verma A. Asakura D.A. Lowe et al. Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice J Clin Invest 130 5 2465 77 32250341 7190912
C.R. Giesige L.M. Wallace K.N. Heller J.O. Eidahl N.Y. Saad A.M. Fowler N.K. Pyne M. Al-Kharsan A. Rashnonejad G.A. Chermahini et al. AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD JCI Insight 3 22 e123538 30429376 6302942
T. Jones P.L. Jones A cre-inducible DUX4 Transgenic mouse model for investigating facioscapulohumeral muscular dystrophy PLoS ONE 13 2 e0192657 29415061 5802938
J.J. McCarthy R. Srikuea T.J. Kirby C.A. Peterson K.A. Esser Inducible Cre Transgenic mouse strain for skeletal muscle-specific gene targeting Skelet Muscle 2 1 8 22564549 3407725
A. Derenne A. Tassin T.H. Nguyen E. De Roeck V. Jenart E. Ansseau A. Belayew F. Coppee A.E. Decleves A. Legrand Induction of a local muscular dystrophy using electroporation in vivo: an easy tool for screening therapeutics Sci Rep 10 1 11301 32647247 7347864
Jones PA. https://myfshd.org/wp-content/uploads/2021/04/myfshd-animal-model-pig1.pdf. 2021.
Y. Nip S.R. Bennett A.A. Smith T.I. Jones P.L. Jones S.J. Tapscott Human DUX4 and Porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD Hum Mol Genet 32 11 1864 74 36728804 10196675
Y. Zhang O.D. King F. Rahimov T.I. Jones C.W. Ward J.P. Kerr N. Liu C.P. Emerson Jr L.M. Kunkel T.A. Partridge et al. Human skeletal muscle xenograft as a new preclinical model for muscle disorders Hum Mol Genet 23 12 3180 8 24452336 4030773
A.L. Mueller A. O’Neill T.I. Jones A. Llach L.A. Rojas P. Sakellariou G. Stadler W.E. Wright D. Eyerman P.L. Jones et al. Muscle xenografts reproduce key molecular features of facioscapulohumeral muscular dystrophy Exp Neurol 320 113011 31306642 6730665
P.G. Hendrickson J.A. Dorais E.J. Grow J.L. Whiddon J.W. Lim C.L. Wike B.D. Weaver C. Pflueger B.R. Emery A.L. Wilcox et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons Nat Genet 49 6 925 34 28459457 5703070
J.L. Whiddon A.T. Langford C.J. Wong J.W. Zhong S.J. Tapscott Conservation and innovation in the DUX4-family gene network Nat Genet 49 6 935 40 28459454 5446306
A. De Iaco E. Planet A. Coluccio S. Verp J. Duc D. Trono DUX-family transcription factors regulate zygotic genome activation in placental mammals Nat Genet 49 6 941 5 28459456 5446900
S. Das B.P. Chadwick Influence of repressive histone and DNA methylation upon D4Z4 transcription in Non-Myogenic cells PLoS ONE 11 7 e0160022 27467759 4965136
O.M. Gannon L. Merida de Long N.A. Saunders DUX4 is derepressed in Late-Differentiating keratinocytes in conjunction with loss of H3K9me3 epigenetic repression J Invest Dermatol 136 6 1299 302 26872601
D. Bosnakovski M.D. Gearhart S.H. Choi M. Kyba Dux facilitates post-implantation development, but is not essential for zygotic genome activation Biol Reprod 104 83 93 32997106
Z. Chen Y. Zhang Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development Nat Genet 51 6 947 51 31133747 6545155
Guo Y, Kitano T, Inoue K, Murano K, Hirose M, Li TD, Sakashita A, Ishizu H, Ogonuki N, Matoba S et al. Obox4 promotes zygotic genome activation upon loss of Dux. eLife 2024, 13:e95856.
M.L. Ruebel K.A. Vincent P.Z. Schall K. Wang K.E. Latham SMCHD1 terminates the first embryonic genome activation event in mouse two-cell embryos and contributes to a transcriptionally repressive state Am J Physiol Cell Physiol 317 4 C655 64 31365290 6850993
M. Percharde C.J. Lin Y. Yin J. Guan G.A. Peixoto A. Bulut-Karslioglu S. Biechele B. Huang X. Shen M. Ramalho-Santos A LINE1-Nucleolin partnership regulates early development and ESC identity Cell 174 2 391 405 29937225 6046266 e319
M. Vega-Sendino F.F. Luttmann T. Olbrich Y. Chen C. Kuenne P. Stein D. Tillo G.I. Carey J. Zhong V. Savy et al. The homeobox transcription factor DUXBL controls exit from totipotency Nat Genet 56 4 697 709 38509386 11149696
D. Bosnakovski E.A. Toso E.T. Ener M.D. Gearhart L. Yin F.F. Luttmann A. Magli K. Shi J. Kim H. Aihara et al. Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein iScience 26 10 107823 37744032 10514451
S. Jiang K. Williams X. Kong W. Zeng N.V. Nguyen X. Ma R. Tawil K. Yokomori A. Mortazavi Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei PLoS Genet 16 5 e1008754 32365093 7224571
T. Yasuda S. Tsuzuki M. Kawazu F. Hayakawa S. Kojima T. Ueno N. Imoto S. Kohsaka A. Kunita K. Doi et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults Nat Genet 48 5 569 74 27019113
Y.F. Liu B.Y. Wang W.N. Zhang J.Y. Huang B.S. Li M. Zhang L. Jiang J.F. Li M.J. Wang Y.J. Dai et al. Genomic profiling of adult and pediatric B-cell acute lymphoblastic leukemia EBioMedicine 8 173 83 27428428 4919728
H. Lilljebjorn R. Henningsson A. Hyrenius-Wittsten L. Olsson C. Orsmark-Pietras S. von Palffy M. Askmyr M. Rissler M. Schrappe G. Cario et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia Nat Commun 7 11790 27265895 4897744
J. Zhang K. McCastlain H. Yoshihara B. Xu Y. Chang M.L. Churchman G. Wu Y. Li L. Wei I. Iacobucci et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia Nat Genet 48 12 1481 9 27776115 5144107
T.I. Jones C.L. Himeda D.P. Perez P.L. Jones Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy Neuromuscul Disord 27 3 221 38 28161093
C.R.S. Banerji M. Panamarova P.S. Zammit DUX4-expressing immortalised FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation Hum Mol Genet 29 2285 99 32242220 7424723
M. Signorelli A.G. Mason K. Mul T. Evangelista H. Mei N. Voermans S.J. Tapscott R. Tsonaka B.G.M. van Engelen S.M. van der Maarel et al. Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients Sci Rep 10 1 17547 33067535 7567883
A.A. Smith Y. Nip S.R. Bennett D.C. Hamm R. Lemmers P.J. van der Vliet M. Setty S.M. van der Maarel S.J. Tapscott DUX4 expression in cancer induces a metastable early embryonic totipotent program Cell Rep 42 9 113114 37691147 10578318
G.L. Chew A.E. Campbell E. De Neef N.A. Sutliff S.C. Shadle S.J. Tapscott R.K. Bradley DUX4 suppresses MHC class I to promote Cancer immune evasion and resistance to checkpoint Blockade Dev Cell 50 5 658 e671657 31327741 6736738
Spens AE, Sutliff NA, Bennett SR, Campbell AE, Tapscott SJ. Human DUX4 and mouse dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction. eLife 2023, 12:e82057.
Pineda JMB, Bradley RK. DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers. eLife 2024, 12:RP89017.
Friedel CC, Whisnant AW, Djakovic L, Rutkowski AJ, Friedl MS, Kluge M, Williamson JC, Sai S, Vidal RO, Sauer S et al. Dissecting herpes simplex virus 1-Induced host shutoff at the RNA level. J Virol 2021, 95(3):e01399-20.
E. Neugebauer A.M. Bastidas-Quintero D. Weidl F. Full Pioneer factors in viral infection Front Immunol 14 1286617 37876935 10591220
M.S. Tihaya K. Mul J. Balog J.C. de Greef S.J. Tapscott R. Tawil J.M. Statland S.M. van der Maarel Facioscapulohumeral muscular dystrophy: the road to targeted therapies Nat Rev Neurol 19 2 91 108 36627512 11578282
Teveroni E, Pellegrino M, Sacconi S, Calandra P, Cascino I, Farioli-Vecchioli S, et al. Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity. J Clin Invest. 2017;127(4):1531–45.
A. Joliot A. Prochiantz Unconventional secretion, gate to Homeoprotein intercellular transfer Front Cell Dev Biology 10 926421
