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A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity.

By Alex Jade McCann, Jieqiong Lou, Mehdi Moustaqil, Ailisa Blum, Frank Fontaine, Hui Liu, Winnie Luu, Peter Koopman, Emma Sierecki, Yann Gambin, Frederic A Meunier, Zhe Liu, Elizabeth Hinde, Mathias Francois

Posted 12 Nov 2020
bioRxiv DOI: 10.1101/2020.11.11.378968

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. ### Competing Interest Statement The authors have declared no competing interest.

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