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

Abstract

BackgroundThe 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.ResultsMicroarray 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.ConclusionsPPARβ/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.

Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-β/δ Modulation of SP1 Promoter Occupancy

“…Microarray Analysis-Total RNA was isolated as previously described (37). Purified RNA was assessed by GeneChip Mouse Gene 2.0 ST array (Affymetrix, Santa Clara, CA) following the manufacturer's recommended procedures.…”

“…Purified RNA was assessed by GeneChip Mouse Gene 2.0 ST array (Affymetrix, Santa Clara, CA) following the manufacturer's recommended procedures. The robust multichip average approach was applied to normalize microarray data as previously described (37). The p value Ͻ 0.05 and a fold change of 1.5 in the intensity of signals were used to identify genes that were significantly regulated by ethanol treatment.…”

Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling

“…Peroxisome proliferator-activated receptors (PPARs 3 : PPARA, PPARD (also referred to as PPAR␤, PPAR␦, PPAR␤/␦, or NUC1), and PPARG) are ligand-activated transcription factors that control a variety of biological processes in dynamic fashion (4). Previous studies showed that all three PPARs are expressed in both somatic and spermatogenic cells in the testis (5-7).…”

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway

“…Gene expression analysis studies in combination with chromatin immunoprecipitation sequencing (ChIP-seq) have identified direct and indirect PPAR-δ regulated genes (21, 22). Well-documented direct targets of PPAR-δ include genes involved in fatty-acid oxidation and lipid metabolism such as Cpt1a , Fabp1 and Pdk4, whereas pro-inflammatory cytokines like TNF-α and IL-6 are regulated indirectly.…”