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2016-03-14 - Colloque/Présentation - poster - Anglais - 1 page(s)

De La Kethulle De Ryove Laurence, Ansseau Eugénie , Nachtegael Charlotte, Pieters Karlien, Vanderplanck Céline, Geens Mieke, Sermon Karen, Wilton Steve, Coppée Frédérique , Lagneaux Laurence, Belayew Alexandra , "The Role of D4Z4-Encoded Proteins in the Osteogenic Differentiation of Mesenchymal Stromal Cells Isolated from Bone Marrow." in 5th International Congress of Myology, Lyon, France, 2016

  • Codes CREF : Biologie moléculaire (DI3111), Pathologies particulières (DI3370), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) Laurence de la Kethulle de Ryhove1, Eugénie Ansseau1, Charlotte Nachtegael1, Karlien Pieters2, Céline Vanderplanck1, Mieke Geens3, Karen Sermon3, Steve Wilton4, Frédérique Coppée1, Laurence Lagneaux2# and Alexandra Belayew1#*. The D4Z4 repeat array in 4q35 is hypomethylated in Facioscapulohumeral muscular dystrophy (FSHD). We have previously identified the Double Homeobox 4 (DUX4) gene within the D4Z4 unit that inappropriately expresses a toxic 52-kDa protein in FSHD muscle cells. DUX4 is also a retrogene that is normally expressed in germline cells and is submitted to repeat-induced silencing in adult tissues. DUX4 mRNAs have been detected in human embryonic and induced pluripotent stem (hES and iPS) cells. We have now investigated whether DUX4 could be expressed in human mesenchymal stromal cells (hMSCs) isolated from bone marrow. These cells can differentiate along several lineages (osteoblasts, chondroblasts, adipocytes,…). We have unexpectedly found that DUX4 expression was induced upon hMSC differentiation to osteoblasts. This process involved 52-kDa DUX4 known in FSHD muscles and a new longer protein form (58 kDa). The 52-kDa DUX4 protein was expressed at very low levels in the undifferentiated and differentiated cells while the 58-kDa DUX4 protein was detected at increasing levels from day 8 to 21 following the induction of osteogenic differentiation. During osteogenic differentiation of human embryonic stem cells (hESC) that carry the FSHD1 genetic defect, a DUX4 mRNA with a more distant 5’ start site was characterized: it presented a 60-codon reading frame extension and encoded the 58-kDa protein (DUX4M60). Transfections of hMSCs with an antisense oligonucleotide targeting DUX4 mRNAs decreased both the 52- and 58-kDa protein levels and confirmed their identity. Gain and loss of function experiments in hMSCs suggested these DUX4 proteins had roles in osteogenic differentiation as evidenced by the alkaline phosphatase activity and calcium deposition. The differentiation was increased by 52-kDa DUX4 but was delayed by 58-kDa DUX4 expression, showing opposite roles in osteoblastic differentiation Neither of these proteins appeared cytotoxic in MSCs.of hMSCs. Several therapeutic approaches for FSHD are being developed that aim to interfere with DUX4 expression. Our present study indicates essential functions in MSC differentiation that should be maintained and demonstrates the need for specific muscle targeting of DUX4-suppressing agents.