| Autor: |
Elizabeth Hinde, Winnie Luu, Jieqiong Lou, Alex Jade McCann, Frederic A. Meunier, Hui Liu, Mathias Francois, Ailisa Blum, Peter Koopman, Emma Sierecki, Mehdi Moustaqil, Zhe Liu, Frank Fontaine, Yann Gambin |
| Rok vydání: |
2020 |
| Předmět: |
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| 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 Syndrome. Combing three single-molecule imaging assays in living cells, 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 chromatin-binding dynamics. The dominant-negative effect is further amplified by recruiting 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 etiology of dominant-negative transcription factor function. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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