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2015-10-06 - Colloque/Présentation - communication orale - Anglais - 1 page(s)

De La Kethulle De Ryhove Laurence , Ansseau Eugénie , Nachtegael C, Pieters Karlien, Vanderplanck Céline, Geens Mieke, Sermon Karen, Wilton D. 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 FSH Society , Boston, USA, 2015

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

Abstract(s) :

(Anglais) The Double Homeobox 4 (DUX4) gene is inappropriately activated 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. In collaboration with Dr.Laurence Lagneaux’s group (Institut J. Bordet, ULB), we investigated whether DUX4 could be expressed in human mesenchymal stromal cells (hMSCs). This group has developed different techniques to isolate hMSCs from bone marrow but also to differentiate them 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 is express in the undifferentiated and differentiated cells while the 58-kDa DUX4 protein is express from day 8 following the induction of the osteogenic differentiation. During osteogenic differentiation of human embryonic stem cells (hESC) that carry the FSHD genetic defect, a DUX4 mRNA with a more distant 5’ start site that presented a 60-codon reading frame extension was characterized 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 delayed by 58-kDa DUX4 expression, but it was increased by 52-kDa DUX4 showing opposite role in osteoblastic differentiation. These data indicate an opposite role for DUX4 protein forms in the osteogenic differentiation 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 not be suppressed and demonstrates the need for specific muscle targeting of DUX4-suppressing agents.