PUBLICATION
Homodimerization regulates an endothelial specific signature of the SOX18 transcription factor
- Authors
- Moustaqil, M., Fontaine, F., Overman, J., McCann, A., Bailey, T.L., Rudolffi Soto, P., Bhumkar, A., Giles, N., Hunter, D.J.B., Gambin, Y., Francois, M., Sierecki, E.
- ID
- ZDB-PUB-181020-12
- Date
- 2018
- Source
- Nucleic acids research 46(21): 11381-11395 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- DNA-Binding Proteins/chemistry
- Endothelium/metabolism
- Mutation
- Mice
- Zebrafish
- Gene Expression Regulation, Developmental
- Endothelial Cells/metabolism
- Zebrafish Proteins/chemistry
- Green Fluorescent Proteins/chemistry
- Protein Domains
- Humans
- Animals
- SOXF Transcription Factors/chemistry*
- Open Reading Frames
- Amino Acid Motifs
- Biosensing Techniques
- Protein Multimerization
- PubMed
- 30335167 Full text @ Nucleic Acids Res.
Citation
Moustaqil, M., Fontaine, F., Overman, J., McCann, A., Bailey, T.L., Rudolffi Soto, P., Bhumkar, A., Giles, N., Hunter, D.J.B., Gambin, Y., Francois, M., Sierecki, E. (2018) Homodimerization regulates an endothelial specific signature of the SOX18 transcription factor. Nucleic acids research. 46(21):11381-11395.
Abstract
During embryogenesis, vascular development relies on a handful of transcription factors that instruct cell fate in a distinct sub-population of the endothelium (1). The SOXF proteins that comprise SOX7, 17 and 18, are molecular switches modulating arterio-venous and lymphatic endothelial differentiation (2,3). Here, we show that, in the SOX-F family, only SOX18 has the ability to switch between a monomeric and a dimeric form. We characterized the SOX18 dimer in binding assays in vitro, and using a split-GFP reporter assay in a zebrafish model system in vivo. We show that SOX18 dimerization is driven by a novel 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 on the chromatin revealed enrichment for a SOX dimer binding motif, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping