Histone deacetylase 9 is a negative regulator of adipogenic differentiation

Tapan K. Chatterjee, Gila Idelman, Victor Blanco, Andra L. Blomkalns, Mark G. Piegore, Daniel S. Weintraub, Santosh Kumar, Srinivas Rajsheker, David Manka, Steven M. Rudich, Yaoliang Tang, David Y. Hui, Rhonda Bassel-Duby, Eric N. Olson, Jerry B. Lingrel, Shuk Mei Ho, Neal L. Weintraub

Research output: Contribution to journalArticle

79 Scopus citations

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 p300HATis 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 p300HAT in the USF1 complex is associated with increased C/EBPαexpression, 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.

Original languageEnglish (US)
Pages (from-to)27836-27847
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number31
DOIs
StatePublished - Aug 5 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chatterjee, T. K., Idelman, G., Blanco, V., Blomkalns, A. L., Piegore, M. G., Weintraub, D. S., Kumar, S., Rajsheker, S., Manka, D., Rudich, S. M., Tang, Y., Hui, D. Y., Bassel-Duby, R., Olson, E. N., Lingrel, J. B., Ho, S. M., & Weintraub, N. L. (2011). Histone deacetylase 9 is a negative regulator of adipogenic differentiation. Journal of Biological Chemistry, 286(31), 27836-27847. https://doi.org/10.1074/jbc.M111.262964