PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

Maria Stahl Madsen, Marjoleine F. Broekema, Martin Rønn Madsen, Arjen Koppen, Anouska Borgman, Cathrin Gräwe, Elisabeth G. K. Thomsen, Denise Westland, Mariette E. G. Kranendonk, Marian Groot Koerkamp, Nicole Hamers, Alexandre M. J. J. Bonvin, José M. Ramos Pittol, Kedar Nath Natarajan, Sander Kersten, Frank C. P. Holstege, Houshang Monajemi, Saskia W. C. Mil, Michiel Vermeulen, Birthe B. Kragelund, David Cassiman, Susanne Mandrup () and Eric Kalkhoven ()
Additional contact information
Maria Stahl Madsen: University of Southern Denmark
Marjoleine F. Broekema: University Medical Center Utrecht, Utrecht University
Martin Rønn Madsen: University of Southern Denmark
Arjen Koppen: University Medical Center Utrecht, Utrecht University
Anouska Borgman: University Medical Center Utrecht, Utrecht University
Cathrin Gräwe: Radboud University Nijmegen
Elisabeth G. K. Thomsen: University of Copenhagen
Denise Westland: University Medical Center Utrecht, Utrecht University
Mariette E. G. Kranendonk: University Medical Center Utrecht, Utrecht University
Marian Groot Koerkamp: University Medical Center Utrecht, Utrecht University
Nicole Hamers: University Medical Center Utrecht, Utrecht University
Alexandre M. J. J. Bonvin: Utrecht University
José M. Ramos Pittol: University Medical Center Utrecht, Utrecht University
Kedar Nath Natarajan: University of Southern Denmark
Sander Kersten: Wageningen University
Frank C. P. Holstege: University Medical Center Utrecht, Utrecht University
Houshang Monajemi: Internal Medicine, Rijnstate Hospital
Saskia W. C. Mil: University Medical Center Utrecht, Utrecht University
Michiel Vermeulen: Radboud University Nijmegen
Birthe B. Kragelund: University of Copenhagen
David Cassiman: Leuven University Hospitals
Susanne Mandrup: University of Southern Denmark
Eric Kalkhoven: University Medical Center Utrecht, Utrecht University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.

Date: 2022
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DOI: 10.1038/s41467-022-34766-9

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