Propagation of adipogenic signals through an epigenomic transition state
- David J. Steger1,2,
- Gregory R. Grant3,4,
- Michael Schupp1,2,
- Takuya Tomaru1,2,
- Martina I. Lefterova1,2,
- Jonathan Schug5,
- Elisabetta Manduchi3,4,
- Christian J. Stoeckert Jr3,4 and
- Mitchell A. Lazar1,2,3,6
- 1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 3Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 4Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 5Genomics and Gene Targeting Core, Penn Diabetes and Endocrinology Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Abstract
The transcriptional mechanisms by which temporary exposure to developmental signals instigates adipocyte differentiation are unknown. During early adipogenesis, we find transient enrichment of the glucocorticoid receptor (GR), CCAAT/enhancer-binding protein β (CEBPβ), p300, mediator subunit 1, and histone H3 acetylation near genes involved in cell proliferation, development, and differentiation, including the gene encoding the master regulator of adipocyte differentiation, peroxisome proliferator-activated receptor γ2 (PPARγ2). Occupancy and enhancer function are triggered by adipogenic signals, and diminish upon their removal. GR, which is important for adipogenesis but need not be active in the mature adipocyte, functions transiently with other enhancer proteins to propagate a new program of gene expression that includes induction of PPARγ2, thereby providing a memory of the earlier adipogenic signal. Thus, the conversion of preadipocyte to adipocyte involves the formation of an epigenomic transition state that is not observed in cells at the beginning or end of the differentiation process.
Keywords
Footnotes
-
↵6 Corresponding author.
E-MAIL lazar{at}mail.med.upenn.edu; FAX (215) 898-5408.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1907110.
-
Supplemental material is available at http://www.genesdev.org.
- Received January 18, 2010.
- Accepted March 30, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press