A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity
| Autor: | Mehdi Moustaqil, Frederic A. Meunier, Alex Jade McCann, Frank Fontaine, Yann Gambin, Peter Koopman, Ailisa Blum, Winnie Luu, Jieqiong Lou, Hui Liu, Mathias Francois, Matthew S Graus, Paulina Rudolffi-Soto, Zhe Liu, Emma Sierecki, Elizabeth Hinde |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Transcription
Genetic AcademicSubjects/SCI00010 Mutant Biology Dominant-Negative Mutation medicine.disease_cause Hypotrichosis Interactome 03 medical and health sciences Mice 0302 clinical medicine Glomerulonephritis Mutant protein Genes Reporter Chlorocebus aethiops Genetics medicine Human Umbilical Vein Endothelial Cells SOXF Transcription Factors Animals Humans MEF2C Gene Regulatory Networks Lymphedema Telangiectasis Luciferases Transcription factor 030304 developmental biology 0303 health sciences Mutation MEF2 Transcription Factors Gene regulation Chromatin and Epigenetics Single Molecule Imaging Chromatin Cell biology Disease Models Animal Gene Expression Regulation COS Cells 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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 defect 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. |
| Databáze: | OpenAIRE |
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