Single molecule tracking videos: SOX18 and its dominant-negative mutant SOX18RaOp
Authors/Creators
- 1. University of Queensland
- 2. University of Melbourne
- 3. University of New South Wales
- 4. University of Sydney
- 5. Janelia Farm Research Campus
Description
Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-Lymphedema-Telangiectasia-Renal Syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.
Notes
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1120381
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1124762
Funding provided by: Australian Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000923
Award Number: LE130100078
Funding provided by: Jacob Haimson Beverly Mecklenburg Lectureship*
Crossref Funder Registry ID:
Award Number:
Funding provided by: Biological Optical Microscopy Platform (BOMP)*
Crossref Funder Registry ID:
Award Number:
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1164000
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1111169
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1155794
Funding provided by: National Health and Medical Research Council
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000925
Award Number: GNT1104461
Funding provided by: Jacob Haimson Beverly Mecklenburg Lectureship
Crossref Funder Registry ID:
Funding provided by: Biological Optical Microscopy Platform (BOMP)
Crossref Funder Registry ID:
Files
SMT_VIDEOSreadme.txt
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Additional details
Related works
- Is cited by
- 10.1101/2020.11.11.378968 (DOI)