Homodimerization regulates an endothelial specific signature of the SOX18 transcription factor
- EMBL Australia Node in Single Molecule Science School of Medical Sciences, The University of New South Wales, Sydney, Australia.
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- 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.