Homodimerization regulates an endothelial specific signature of the SOX18 transcription factor

Moustaqil M1, Fontaine F2, Overman J2, MacCann A2, Bailey TL3, Rudolffi Soto P1, Gambin Y1, Francois M2 and Sierecki E1

  1. EMBL Australia Node in Single Molecule Science School of Medical Sciences, The University of New South Wales, Sydney, Australia.
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
  3. Department of Pharmacology, School of Medicine, University of Nevada, Reno, USA.

During embryogenesis, vascular development relies on a handful of transcription factors that instruct cell fate in a distinct sub-population of the endothelium. The SOXF proteins that comprise SOX7, 17 and 18, are molecular switches modulating arterio-venous and lymphatic endothelial differentiation. We recently found that in the SOX-F family, SOX18 alone has the ability to switch between a monomeric and a dimeric form, using in vitro binding assays and a split-GFP reporter assay in a zebrafish model system in vivo. SOX18 dimerization is driven by a newly identified motif located in the vicinity of the C-terminus of the DNA binding region. Insertion of this motif in a SOX7 monomer forced its assembly into a dimer. Genome-wide analysis of SOX18 binding locations revealed enrichment for a SOX dimer binding motif on the chromatin, correlating with genes with a strong endothelial signature. Using a SOX18 small molecule inhibitor that disrupts dimerization, we revealed that dimerization is important for transcription. Overall, we show that dimerization is a specific feature of SOX18 that enables the recruitment of key endothelial transcription factors, and refines the selectivity of the binding to discrete genomic locations assigned to endothelial specific genes.