title: Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60.
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.
authors.affiliation: Section Metabolic Diseases, Molecular Cancer Research, and Netherlands Metabolomics Centre, University Medical Centre Utrecht, Utrecht 3584 CG, The Netherlands.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Arjen
authors.initials: A
authors.lastname: Koppen
authors.forename: Maryam
authors.initials: M
authors.lastname: Rakhshandehroo
authors.forename: Ismayil
authors.initials: I
authors.lastname: Tasdelen
authors.forename: Stan F
authors.initials: SF
authors.lastname: van de Graaf
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
authors.forename: Olivier
authors.initials: O
authors.lastname: van Beekum
authors.forename: Nicole
authors.initials: N
authors.lastname: Hamers
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.forename: Celia R
authors.initials: CR
authors.lastname: Berkers
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Arjan B
authors.initials: AB
authors.lastname: Brenkman
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Eric
authors.initials: E
authors.lastname: Kalkhoven
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse