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Molecular and Cellular Biology, July 2009, p. 3544-3555, Vol. 29, No. 13
0270-7306/09/$08.00+0 doi:10.1128/MCB.01856-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
The Peroxisome Proliferator-Activated Receptor 
/Retinoid X Receptor 
Heterodimer Targets the Histone Modification Enzyme PR-Set7/Setd8 Gene and Regulates Adipogenesis through a Positive Feedback Loop
,
Ken-ichi Wakabayashi,1,4
Masashi Okamura,2
Shuichi Tsutsumi,1
Naoko S. Nishikawa,3
Toshiya Tanaka,2
Iori Sakakibara,2
Jun-ichi Kitakami,3
Sigeo Ihara,3
Yuichi Hashimoto,4
Takao Hamakubo,5
Tatsuhiko Kodama,6
Hiroyuki Aburatani,1 and
Juro Sakai2*
Genome Science Division,1 Metabolism and Endocrinology Division,2 Dynamical Bioinformatics Division,3 Membrane Protein Division,5 Vascular System Division, Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan,6 Institute of Molecular & Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan4
Received 5 December 2008/ Returned for modification 17 January 2009/ Accepted 18 April 2009
Control of cell differentiation occurs through transcriptional mechanisms and through epigenetic modification. Using a chromatin immunoprecipitation-on-chip approach, we performed a genome-wide search for target genes of peroxisome proliferator-activated receptor 
(PPAR) and its partner protein retinoid X receptor 
during adipogenesis. We show that these two receptors target several genes that encode histone lysine methyltransferase SET domain proteins. The histone H4 Lys 20 (H4K20) monomethyltransferase PR-Set7/Setd8 gene is upregulated by PPAR during adipogenesis, and the knockdown of PR-Set7/Setd8 suppressed adipogenesis. Intriguingly, monomethylated H4K20 (H4K20me1) levels are robustly increased toward the end of differentiation. PR-Set7/Setd8 positively regulates the expression of PPAR and its targets through H4K20 monomethylation. Furthermore, the activation of PPAR transcriptional activity leads to the induction of H4K20me1 modification of PPAR and its targets and thereby promotes adipogenesis. We also show that PPAR targets PPAR2 and promotes its gene expression through H4K20 monomethylation. Our results connect transcriptional regulation and epigenetic chromatin modulation through H4K20 monomethylation during adipogenesis through a feedback loop.
* Corresponding author. Mailing address: Metabolism and Endocrinology Division, Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan. Phone: 81-3-5452-5472. Fax: 81-3-5452-5429. E-mail: jmsakai-tky{at}umin.ac.jp
Published ahead of print on 4 May 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, July 2009, p. 3544-3555, Vol. 29, No. 13
0270-7306/09/$08.00+0 doi:10.1128/MCB.01856-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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