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Open Access Highly Accessed Research article

Analysis of the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) cistrome reveals novel co-regulatory role of ATF4

Combiz Khozoie1, Michael G Borland14, Bokai Zhu1, Songjoon Baek2, Sam John25, Gordon L Hager2, Yatrik M Shah36, Frank J Gonzalez3 and Jeffrey M Peters1*

Author Affiliations

1 Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802, USA

2 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD, 20892, USA

3 Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, 20892, USA

4 Present address: Department of Chemistry and Biochemistry, Bloomsburg University of Pennsylvania, Bloomsburg, PA, USA

5 Present address: Genome Sciences, University of Washington, Seattle, WA, USA

6 Present address: Department of Physiology, University of Michigan, Ann Arbor, MI, USA

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BMC Genomics 2012, 13:665  doi:10.1186/1471-2164-13-665

Published: 24 November 2012

Abstract

Background

The present study coupled expression profiling with chromatin immunoprecipitation sequencing (ChIP-seq) to examine peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)-dependent regulation of gene expression in mouse keratinocytes, a cell type that expresses PPARβ/δ in high concentration.

Results

Microarray analysis elucidated eight different types of regulation that modulated PPARβ/δ-dependent gene expression of 612 genes ranging from repression or activation without an exogenous ligand, repression or activation with an exogenous ligand, or a combination of these effects. Bioinformatic analysis of ChIP-seq data demonstrated promoter occupancy of PPARβ/δ for some of these genes, and also identified the presence of other transcription factor binding sites in close proximity to PPARβ/δ bound to chromatin. For some types of regulation, ATF4 is required for ligand-dependent induction of PPARβ/δ target genes.

Conclusions

PPARβ/δ regulates constitutive expression of genes in keratinocytes, thus suggesting the presence of one or more endogenous ligands. The diversity in the types of gene regulation carried out by PPARβ/δ is consistent with dynamic binding and interactions with chromatin and indicates the presence of complex regulatory networks in cells expressing high levels of this nuclear receptor such as keratinocytes. Results from these studies are the first to demonstrate that differences in DNA binding of other transcription factors can directly influence the transcriptional activity of PPARβ/δ.

Keywords:
Peroxisome proliferator-activated receptor-β/δ; Gene expression; Keratinocytes