title: Histone deacetylase 9 is a negative regulator of adipogenic differentiation.
abstract: Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPα gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPα promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPα expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a deacetylase-independent mechanism.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, University of Cincinnati, Cincinnati, Ohio 45267, USA. tapan.chatterjee@uc.edu
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Chatterjee
authors.forename: Gila
authors.initials: G
authors.lastname: Idelman
authors.forename: Victor
authors.initials: V
authors.lastname: Blanco
authors.forename: Andra L
authors.initials: AL
authors.lastname: Blomkalns
authors.forename: Mark G
authors.initials: MG
authors.lastname: Piegore
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Weintraub
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rajsheker
authors.forename: David
authors.initials: D
authors.lastname: Manka
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rudich
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D015536:Down-Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases