The Peroxisome Proliferator-Activated Receptor γ/Retinoid X Receptor α Heterodimer Targets the Histone Modification Enzyme PR-Set7/Setd8 Gene and Regulates Adipogenesis through a Positive Feedback Loop

Abstract

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 γ (PPARγ) and its partner protein retinoid X receptor α 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 PPARγ 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 PPARγ and its targets through H4K20 monomethylation. Furthermore, the activation of PPARγ transcriptional activity leads to the induction of H4K20me1 modification of PPARγ and its targets and thereby promotes adipogenesis. We also show that PPARγ targets PPARγ2 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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Rob Rawson for critical reading of the manuscript; Takeshi Inagaki for helpful discussion; and Hiroko Meguro, Aoi Uchida, and Hiromi Kudo for technical assistance.

This study was supported in part by the Translational Systems Biology and Medicine Initiative (TSBMI); a Grant-in-Aid for Scientific Research, a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan; grants from the Program of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO); and the NFAT project of New Energy and Industrial Technology Development Organization (NEDO). K.W. is a recipient of the JSPS Research Fellowship for Young Scientists.