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DUX4

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https://www.readbyqxmd.com/read/29773604/transcriptional-activities-of-dux4-fusions-in-b-cell-acute-lymphoblastic-leukemia
#1
Yosuke Tanaka, Masahito Kawazu, Takahiko Yasuda, Miki Tamura, Fumihiko Hayakawa, Shinya Kojima, Toshihide Ueno, Hitoshi Kiyoi, Tomoki Naoe, Hiroyuki Mano
No abstract text is available yet for this article.
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29759937/identification-of-epigenetic-regulators-of-dux4-fl-for-targeted-therapy-of-facioscapulohumeral-muscular-dystrophy
#2
Charis L Himeda, Takako I Jones, Ching-Man Virbasius, Lihua Julie Zhu, Michael R Green, Peter L Jones
Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic de-repression of the disease locus, leading to pathogenic misexpression of the DUX4 gene in skeletal muscle. While the factors and pathways involved in normal repression of the FSHD locus in healthy cells have been well characterized, very little is known about those responsible for the aberrant activation of DUX4-fl in FSHD myocytes. Reasoning that DUX4-fl activators might represent useful targets for small molecule inhibition, we performed a highly targeted, candidate-based screen of epigenetic regulators in primary FSHD myocytes...
April 26, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29751519/targeting-the-polyadenylation-signal-of-pre-mrna-a-new-gene-silencing-approach-for-facioscapulohumeral-dystrophy
#3
REVIEW
Anne-Charlotte Marsollier, Romain Joubert, Virginie Mariot, Julie Dumonceaux
Facioscapulohumeral dystrophy (FSHD) is characterized by the contraction of the D4Z4 array located in the sub-telomeric region of the chromosome 4, leading to the aberrant expression of the DUX4 transcription factor and the mis-regulation of hundreds of genes. Several therapeutic strategies have been proposed among which the possibility to target the polyadenylation signal to silence the causative gene of the disease. Indeed, defects in mRNA polyadenylation leads to an alteration of the transcription termination, a disruption of mRNA transport from the nucleus to the cytoplasm decreasing the mRNA stability and translation efficiency...
May 3, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29741619/small-noncoding-rnas-in-fshd2-muscle-cells-reveal-both-dux4-and-smchd1-specific-signatures
#4
Jong-Won Lim, Chao-Jen Wong, Zizhen Yao, Rabi Tawil, Silvère M van der Maarel, Daniel G Miller, Stephen J Tapscott, Galina N Filippova
Facioscapulohumeral muscular dystrophy (FSHD) is caused by insufficient epigenetic repression of D4Z4 macrosatellite repeat where DUX4, an FSHD causing gene is embedded. There are two forms of FSHD, FSHD1 with contraction of D4Z4 repeat and FSHD2 with chromatin compaction defects mostly due to SMCHD1 mutation. Previous reports showed DUX4-induced gene expression changes as well as changes in microRNA expression in FSHD muscle cells. However, a genome wide analysis of small noncoding RNAs that might be regulated by DUX4 or by mutations in SMCHD1 has not been reported yet...
May 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29718206/facioscapulohumeral-dystrophy-activating-an-early-embryonic-transcriptional-program-in-human-skeletal-muscle
#5
Amy E Campbell, Andrea Belleville, Rebecca Resnick, Sean C Shadle, Stephen J Tapscott
Facioscapulohumeral dystrophy (FSHD) is the third most prevalent muscular dystrophy. A progressive disease, it presents clinically as weakness and wasting of the face, shoulder, and upper arm muscles, with later involvement of the trunk and lower extremities. FSHD develops through complex genetic and epigenetic events that converge on a common mechanism of toxicity with mis-expression of the transcription factor double homeobox 4 (DUX4). There is currently no treatment available for FSHD. However, the consensus that ectopic DUX4 expression in skeletal muscle is the root cause of FSHD pathophysiology has allowed research efforts to turn towards cultivating a deeper understanding of DUX4 biology and the pathways that underlie FSHD muscle pathology, and to translational studies aimed at developing targeted therapeutics using ever more sophisticated cell and animal-based models of FSHD...
April 28, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29618456/functional-domains-of-the-fshd-associated-dux4-protein
#6
Hiroaki Mitsuhashi, Satoshi Ishimaru, Sachiko Homma, Bryant Yu, Yuki Honma, Mary Lou Beermann, Jeffrey Boone Miller
Aberrant expression of the full-length isoform of DUX4 (DUX4-FL) appears to underlie pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). DUX4-FL is a transcription factor and ectopic expression of DUX4-FL is toxic to most cells. Previous studies showed that DUX4-FL-induced pathology requires intact homeodomains and that transcriptional activation required the C-terminal region. In this study, we further examined the functional domains of DUX4 by generating mutant, deletion, and fusion variants of DUX4...
April 4, 2018: Biology Open
https://www.readbyqxmd.com/read/29572508/structural-basis-of-dux4-igh-driven-transactivation
#7
Xue Dong, Weina Zhang, Haiyan Wu, Jinyan Huang, Ming Zhang, Pengran Wang, Hao Zhang, Zhu Chen, Sai-Juan Chen, Guoyu Meng
Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERGalt through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNADRE -bound DUX4HD2 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox...
March 15, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29563141/monosomy-18p-is-a-risk-factor-for-facioscapulohumeral-dystrophy
#8
Judit Balog, Remko Goossens, Richard J L F Lemmers, Kirsten R Straasheijm, Patrick J van der Vliet, Anita van den Heuvel, Chiara Cambieri, Nicolas Capet, Léonard Feasson, Veronique Manel, Julian Contet, Marjolein Kriek, Colleen M Donlin-Smith, Claudia A L Ruivenkamp, Patricia Heard, Stephen J Tapscott, Jannine D Cody, Rabi Tawil, Sabrina Sacconi, Silvère M van der Maarel
BACKGROUND: 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 ( SMCHD1 ) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2)...
March 21, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29533464/genetic-analyses-of-undifferentiated-small-round-cell-sarcoma-identifies-a-novel-sarcoma-subtype-with-a-recurrent-crtc1-ss18-gene-fusion
#9
Abdullah Alholle, Marie Karanian, Anna T Brini, Mark R Morris, Vinodh Kannappan, Stefania Niada, Angela Niblett, Dominique Ranchère-Vince, Daniel Pissaloux, Christophe Delfour, Aurelie Maran-Gonzalez, Cristina R Antonescu, Vaiyapuri Sumathi, Franck Tirode, Farida Latif
In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation...
June 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29533181/nurd-and-caf-1-mediated-silencing-of-the-d4z4-array-is-modulated-by-dux4-induced-mbd3l-proteins
#10
Amy E Campbell, Sean C Shadle, Sujatha Jagannathan, Jong-Won Lim, Rebecca Resnick, Rabi Tawil, Silvère M van der Maarel, Stephen J Tapscott
The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins...
March 13, 2018: ELife
https://www.readbyqxmd.com/read/29480450/-ewing-sarcomas-and-ewing-like-sarcomas-new-aspects
#11
REVIEW
K Specht, W Hartmann
Sarcomas of the Ewing family of tumors are aggressive neoplasms occurring in bone and soft tissue of mostly children and young adults. Classical Ewing sarcomas are pathognomonically characterized by fusions between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4 or FEV). Less frequent cases designated as Ewing-like sarcomas show different genetic rearrangements between EWSR1 and non-ETS genes (NFATC2, POU5F1, SMARCA5, PATZ, ZSG, SP3). Moreover, new molecular alterations biologically unrelated to Ewing sarcomas have recently been described in the category of undifferentiated round cell sarcomas including CIC-DUX4 fusions or BCOR alterations, each carrying unique gene expression signatures...
March 2018: Der Pathologe
https://www.readbyqxmd.com/read/29478599/facioscapulohumeral-muscular-dystrophy
#12
Rabi Tawil
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29472544/author-correction-muscle-pathology-from-stochastic-low-level-dux4-expression-in-an-fshd-mouse-model
#13
Darko Bosnakovski, Sunny S K Chan, Olivia O Recht, Lynn M Hartweck, Collin J Gustafson, Laura L Athman, Dawn A Lowe, Michael Kyba
In the originally published version of this Article, an incorrect grant number, RO1 NS083549, was acknowledged. The correct grant number is RO1 AR055685. This error has now been corrected in both the PDF and HTML versions of the Article.
February 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29431183/transcriptomic-definition-of-molecular-subgroups-of-small-round-cell-sarcomas
#14
Sarah Watson, Virginie Perrin, Delphine Guillemot, Stephanie Reynaud, Jean-Michel Coindre, Marie Karanian, Jean-Marc Guinebretière, Paul Freneaux, François Le Loarer, Megane Bouvet, Louise Galmiche-Rolland, Frédérique Larousserie, Elisabeth Longchampt, Dominique Ranchere-Vince, Gaelle Pierron, Olivier Delattre, Franck Tirode
Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups...
May 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29416716/robust-diagnosis-of-ewing-sarcoma-by-immunohistochemical-detection-of-super-enhancer-driven-ewsr1-ets-targets
#15
Michaela C Baldauf, Martin F Orth, Marlene Dallmayer, Aruna Marchetto, Julia S Gerke, Rebeca Alba Rubio, Merve M Kiran, Julian Musa, Maximilian M L Knott, Shunya Ohmura, Jing Li, Nusret Akpolat, Ayse N Akatli, Özlem Özen, Uta Dirksen, Wolfgang Hartmann, Enrique de Alava, Daniel Baumhoer, Giuseppina Sannino, Thomas Kirchner, Thomas G P Grünewald
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4- , BCOR-CCNB3- , EWSR1-NFATc2- , and EWSR1-ETS -translocated sarcomas are distinct entities, and revealed that ATP1A1 , BCL11B , and GLG1 constitute specific markers for Ewing sarcoma...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29415061/a-cre-inducible-dux4-transgenic-mouse-model-for-investigating-facioscapulohumeral-muscular-dystrophy
#16
Takako Jones, Peter L Jones
The Double homeobox 4 (DUX4) gene is an important regulator of early human development and its aberrant expression is causal for facioscapulohumeral muscular dystrophy (FSHD). The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. Regardless, the somatic cytotoxicity caused by DUX4 expression is conserved when expressed in cells and animals ranging from fly to mouse. Thus, viable animal models based on DUX4-fl expression have been difficult to generate due in large part to overt developmental toxicity of low DUX4-fl expression from leaky transgenes...
2018: PloS One
https://www.readbyqxmd.com/read/29387734/pre-clinical-safety-and-off-target-studies-to-support-translation-of-aav-mediated-rnai-therapy-for-fshd
#17
Lindsay M Wallace, Nizar Y Saad, Nettie K Pyne, Allison M Fowler, Jocelyn O Eidahl, Jacqueline S Domire, Danielle A Griffin, Adam C Herman, Zarife Sahenk, Louise R Rodino-Klapac, Scott Q Harper
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29330417/high-stap1-expression-in-dux4-rearranged-cases-is-not-suitable-as-therapeutic-target-in-pediatric-b-cell-precursor-acute-lymphoblastic-leukemia
#18
Elisabeth M P Steeghs, Marjolein Bakker, Alex Q Hoogkamer, Judith M Boer, Quirine J Hartman, Femke Stalpers, Gabriele Escherich, Valerie de Haas, Hester A de Groot-Kruseman, Rob Pieters, Monique L den Boer
Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified ('B-other') cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1, an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1-like and non-BCR-ABL1-like B-other cases...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29329560/overexpression-of-the-double-homeodomain-protein-dux4c-interferes-with-myofibrillogenesis-and-induces-clustering-of-myonuclei
#19
Céline Vanderplanck, Alexandra Tassin, Eugénie Ansseau, Sébastien Charron, Armelle Wauters, Céline Lancelot, Kelly Vancutsem, Dalila Laoudj-Chenivesse, Alexandra Belayew, Frédérique Coppée
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initiates a gene deregulation cascade. FSHD primary myoblasts differentiate into either atrophic or disorganized myotubes. DUX4 expression induces atrophic myotubes and associated FSHD markers...
January 12, 2018: Skeletal Muscle
https://www.readbyqxmd.com/read/29300189/bcor-ccnb3-fusion-positive-sarcomas-a-clinicopathologic-and-molecular-analysis-of-36-cases-with-comparison-to-morphologic-spectrum-and-clinical-behavior-of-other-round-cell-sarcomas
#20
Yu-Chien Kao, Adepitan A Owosho, Yun-Shao Sung, Lei Zhang, Yumi Fujisawa, Jen-Chieh Lee, Leonard Wexler, Pedram Argani, David Swanson, Brendan C Dickson, Christopher D M Fletcher, Cristina R Antonescu
BCOR-CCNB3 sarcoma (BCS) is a recently defined genetic entity among undifferentiated round cell sarcomas, which was initially classified as and treated similarly to the Ewing sarcoma (ES) family of tumors. In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3. To further investigate the pathologic features, clinical behavior, and their relationship to other round cell sarcomas, we collected 36 molecularly confirmed BCSs for a detailed histologic and immunohistochemical analysis...
October 25, 2017: American Journal of Surgical Pathology
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