Dux4 controls migration of mesenchymal stem cells through the Cxcr4-Sdf1 axis.

Petr Dmitriev,Alexandra Belayew,Thomas Robert,Marc Lipinski,Andrei Vasiliev,Gilles Carnac,Ekaterina Kiseleva,Philippe Dessen,Andrei Pichugin,Dalila Laoudj-Chenivesse,Frédérique Coppée,Yegor S Vassetzky,Evgeny Ivashkin,Olga Kharchenko

doi:10.18632/oncotarget.11368

Abstract

We performed transcriptome profiling of human immortalized myoblasts (MB) transiently expressing double homeobox transcription factor 4 (DUX4) and double homeobox transcription factor 4 centromeric (DUX4c) and identified 114 and 70 genes differentially expressed in DUX4- and DUX4c-transfected myoblasts, respectively. A significant number of differentially expressed genes were involved in inflammation, cellular migration and chemotaxis suggesting a role for DUX4 and DUX4c in these processes. DUX4 but not DUX4c overexpression resulted in upregulation of the CXCR4 (C-X-C motif Receptor 4) and CXCL12 (C-X-C motif ligand 12 also known as SDF1) expression in human immortalized myoblasts. In a Transwell cell migration assay, human bone marrow-derived mesenchymal stem cells (BMSCs) were migrating more efficiently towards human immortalized myoblasts overexpressing DUX4 as compared to controls; the migration efficiency of DUX4-transfected BMSCs was also increased. DUX4c overexpression in myoblasts or in BMSCs had no impact on the rate of BMSC migration. Antibodies against SDF1 and CXCR4 blocked the positive effect of DUX4 overexpression on BMSC migration. We propose that DUX4 controls the cellular migration of mesenchymal stem cells through the CXCR4 receptor.

Highlights

Human genome harbors 333 genes and pseudogenes with homeobox sequences encoding homeodomain DNA binding motif
double homeobox transcription factor 4 (DUX4) but not double homeobox transcription factor 4 centromeric (DUX4c) overexpression resulted in upregulation of the CXCR4 (C-X-C motif Receptor 4) and CXCL12 (C-X-C motif ligand 12 known as Stromalderived factor 1 (SDF1)) expression in human immortalized myoblasts
We argued that the difference in transcriptome profiles of DUX4 and DUX4c might help us to better understand the functional differences between these two proteins

Summary

Introduction

Human genome harbors 333 genes and pseudogenes with homeobox sequences encoding homeodomain DNA binding motif. The double homeobox (DUX) family is one of the most enigmatic. DUX family members numbered from 1 to 5 [2,3,4] are encoded within tandem repeats of macrosatellite DNA and their multiple polymorphic copies are spread over human genome. Two other members of the DUX family, DUXA [5] and DUXB [6] are single-copy genes encoded on chromosome 19 and 16, respectively. Double homeobox protein 4 (DUX4) and its nearly identical homologue DUX4 centromeric (DUX4c) are the best known of all DUX proteins (for review see [7]). The single-copy of DUX4c gene is located 42 kb proximally to D4Z4 array on chromosome 4q35 [10]

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Conclusion