Journal article

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

Alex J McCann, Jieqiong Lou, Mehdi Moustaqil, Matthew S Graus, Ailisa Blum, Frank Fontaine, Hui Liu, Winnie Luu, Paulina Rudolffi-Soto, Peter Koopman, Emma Sierecki, Yann Gambin, Frederic A Meunier, Zhe Liu, Elizabeth Hinde, Mathias Francois

NUCLEIC ACIDS RESEARCH | OXFORD UNIV PRESS | Published : 2021

Abstract

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 sy..

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Grants

Awarded by National Health and Medical Research Council


Awarded by Australian Research Council


Awarded by Australian Government through Australian Research Council LIEF Grant


Funding Acknowledgements

National Health and Medical Research Council [GNT1120381 to F.A.M., GNT1164000 to E.H. and M.F., GNT1104461 to E.H.]; Australian Research Council [DP180101387 to E.H.]; F.A.M. is a National Health and Medical Research Council Senior Research Fellow [GNT1155794]; M.F. and E.H. are National Health and Medical Research Council Career Development Fellows [GNT1111169 to M.F. and GNT1124762 to E.H.]; Jacob Haimson Beverly Mecklenburg Lectureship [to E.H.]; imaging was performed at the Queensland Brain Institute's Advanced Microscopy Facility, generously supported by the Australian Government through Australian Research Council LIEF Grant [LE130100078 to F.A.M.]; Biological Optical Microscopy Platform (BOMP) at the University of Melbourne. Funding for open access charge: National Health and Medical Research Council [NHMRCAPP116400].