Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

Yuan Gao, Arjen Koppen, Maryam Rakhshandehroo, Ismayil Tasdelen, Stan F. van de Graaf, Jorg van Loosdregt, Olivier van Beekum, Nicole Hamers, Dik van Leenen, Celia R. Berkers, Ruud Berger, Frank C.P. Holstege, Paul J. Coffer, Arjan B. Brenkman, Huib Ovaa and Eric Kalkhoven ()
Additional contact information
Yuan Gao: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Arjen Koppen: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Maryam Rakhshandehroo: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Ismayil Tasdelen: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Stan F. van de Graaf: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Jorg van Loosdregt: Center for Molecular & Cellular Intervention, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Olivier van Beekum: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Nicole Hamers: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Dik van Leenen: Molecular Cancer Research, University Medical Centre Utrecht
Celia R. Berkers: The Netherlands Cancer Institute
Ruud Berger: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Frank C.P. Holstege: Molecular Cancer Research, University Medical Centre Utrecht
Paul J. Coffer: Center for Molecular & Cellular Intervention, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Arjan B. Brenkman: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht
Huib Ovaa: The Netherlands Cancer Institute
Eric Kalkhoven: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis.

Date: 2013
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DOI: 10.1038/ncomms3656

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