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Integrative and Systemic Approaches for Evaluating Pparβ/Δ (PPARD)

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Integrative and Systemic Approaches for Evaluating Pparβ/Δ (PPARD) Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function Greta MP Giordano Attianese and Béatrice Desvergne Center for Integrative Genomics, University of Lausanne, Switzerland Footnotes: Corresponding author, BD: [email protected] Competing interests: The authors declare no competing financial interests Author contributions: Both authors have been involved in drafting the manuscript and revising it critically. Received December 5, 2014; Accepted March 9, 2015; Published April 27, 2015 Copyright © 2015 Giordano Attianese and Desvergne. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Abbreviations: αMyHC, α-Myosin Heavy Chain; BCL6, B-cell lymphoma 6 protein; BAT, Brown adipose tissue; ChIP, Chromatin Immunoprecipitation; CHD, Coronary heart disease; DBD, DNA-binding domain; FAO, Fatty Acid Oxidation; FA, Fatty Acid; GSIS, Glucose-stimulated insulin secretion; HSC, Hematopoietic Stem cells; H&E, Hematoxylin and Eosin; HDAC1, Histone deacetylase 1; LBD, Ligand binding domain; MCP1, Monocyte chemotactic protein 1; NFkB, Nuclear factor kappa-light-chain- enhancer of activated B cells; NR, Nuclear Receptor; NCoR1, Nuclear receptor co-repressor 1; PPARs, Peroxisome proliferator- activated receptors; PPRE, PPAR-responsive element; RER, Respiratory Exchange Ratio; RA, Retinoic Acid; RXR, Retinoid X receptor; SMRT, Silencing mediator of retinoic acid and thyroid hormone receptors; SNPs, Single Nucleotide Polymorphisms; SUMO, Small Ubiquitin-like Modifier; TZDs, Thiazolidinediones; TR, Thyroid hormone receptor; TG, Triglycerides; VLDL, Very large density lipoprotein; WOSCOPS, West of Scotland Coronary Prevention Study; WAT, White adipose tissue. Citation: Giordano Attianese G and Desvergne B (2015) Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function. Nucl Recept Signal 13, e001. doi:10.1621/nrs.13001 Keywords: PPAR β/δ, Systems Biology, nuclear receptor, ChIP The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes ( α, β/δ and γ) have been identified, among which PPAR β/δ (PPARD) is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPAR β/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPAR β/δ-interacting corepressor or coactivator complexes and PPAR β/δ protein post- translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPAR β/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPAR β/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding. Introduction Several qualities make PPAR β/δ an interesting Systems biology aims at deciphering complex molecule to explore using system approaches: its biological units by aggregating biological information ubiquitous expression, the rather broad and poorly of various natures (gene, RNA, protein) in order to specific nature of its ligands (mainly unsaturated free gain the most comprehensive view of the events that fatty acids) and the fundamental functions that shape life. Another way of saying this is that systems PPAR β/δ controls, such as energy metabolism or cell biology aims to understand how a biological system, survival. Herein, we will start with a chapter made up of multiple interacting linear or non-linear concerning the gene, its structure and evolutionary pathways, behaves, and explains the global pattern history, and the main classical properties of PPAR β/δ observable at the level of the organism. The present as a transcription factor. We will then proceed with the review compiles a diversity of details regarding the systemic and integrative views that mouse models activity of peroxisome proliferator-activated receptor carrying alterations of PPAR β/δ activities provide. The β/δ (PPAR β/δ), viewed at the system level. third part will describe the global and unbiased Nuclear Receptor Signaling | www.nrsignaling.org NRS | 2015 | Vol. 13 | doi:10.1621/nrs.13001 | 1 Review PPAR β/δ: integrative and systemic approaches approaches that bridge a system view and molecular [Yoshikawa et al., 1996], and Ppard has been mechanisms. These approaches encompass assigned to chromosome 17 in mouse. The six exons microarray and genome-wide Chromatin in the 3’ part encode the full PPAR β/δ protein. Immunoprecipitation (ChIP). This review will end with the description of polymorphisms in the human PPAR β/δ protein structure PPARD gene that are associated with various pathologies. Like most NRs, the PPAR protein structure consists of four main domains: the unstructured N-terminal A/B- Molecular properties of PPAR β/δ domain, the C-domain folded in two zinc fingers which corresponds to the DNA-binding domain (DBD), the PPAR β/δ ( PPARD ) gene D-domain or hinge region, and finally the E-domain forming a bundle of helices and stranded beta-sheet, Shortly after the characterization of a new nuclear which accommodates a ligand binding pocket. While receptor (NR) involved in the peroxisome proliferation the A/B-and D-domains are only poorly conserved response to some chemicals in mice, which was between the PPAR isotypes, the C- and E-domains accordingly referred to as peroxisome-proliferator share a high degree of sequence and structural activated receptor (PPAR) [Issemann and Green, homology (reviewed in [Escher and Wahli, 2000]). 1990], three PPAR genes, α ( PPARA ), β ( PPARD ) and γ ( PPARG ), were identified in Xenopus laevi Whether and by which mechanism the N-terminal [Krey et al., 1993]. When characterized in mouse, rat activator domain (AF1) of PPARs may regulate or human, the mammalian PPAR α and PPAR γ genes transcriptional activity remains debated. This domain were easily identified, while the third gene was less appears to be a determinant for PPAR subtype- clearly homologous to the Xenopus PPAR β and was specific activity [Bugge et al., 2009; Castillo et al., alternatively called NUC-1 in human [Schmidt et al., 1999; Hummasti and Tontonoz, 2006], also restricting 1992], fatty acid activated receptor (FAAR) [Amri et the number of genes transcriptionally regulated by al., 1995] in mice, and lastly PPAR δ [Evans et al., each of the PPAR subtypes [Hummasti and Tontonoz, 2004]. It now appears clear that they are indeed 2006]. homologous to the Xenopus PPAR β [Germain et al., 2006; Laudet, 1997]. These laborious identification The ligand binding domain (LBD) in all three PPARs efforts explain the different names for PPAR β/δ in the is a very large Y-shaped cavity (about 1400 cubic literature. angstroms) as compared to other NRs, and this characteristic allows the PPARs to interact with PPARs belong to a subfamily of the NR superfamily, numerous structurally-distinct ligands [Nolte et al., together with the thyroid hormone receptors, retinoic 1998]. However, a novel aspect of the PPAR β/δ acid (RA), vitamin D, ecdysone, and the orphan pocket is the narrowness of one of the Y arms, which receptors Rev-ErbA α (5ear1;NR1D1) and E75 cannot accommodate bulky polar heads [Xu et al., (NR1D3, from Drosophila). The latter two represent 2001; Zoete et al., 2007] such as Thiazolidinediones the closest relatives of the PPARs [Laudet et al., (TZDs) and L-tyrosine-based agonists. When the 1992]. The ancestral genes in this subfamily human PPAR β/δ LBD was first crystallized in absence appeared more than 500 million years ago [Knoll, of ligand, the crystals indicated the presence of 1992], followed by further duplication. The ancestral vaccenic acid, of bacterial origin, in the ligand pocket thyroid hormone receptor (TR) gene duplicated into [Fyffe et al., 2006]. Crystallization in the presence of two genes, TR α (NR1A1) and TR β (NR1A2), and the the potent and selective PPAR β/δ ligand GW0742 ancestral retinoic acid receptor (RAR) gene was later performed [Batista et al., 2012] and both duplicated into three genes, RAR α (NR1B1), RAR β studies suggest that two residues in the hormone (NR1B2), and RAR γ (NR1B3). Similarly, the three binding pocket (Val312 and Ile328) are important for PPAR loci, α, β, and γ, appeared during this second ligand-selective binding to PPAR β/δ. Finally, in the period [Laudet et al., 1992], with the duplication true absence of ligand, the structure of PPAR β/δ events likely being contemporaneous with the seems to correspond to an equilibrium of different appearance of the early vertebrates [Keese and conformations, among which are those favoring Gibbs, 1992]. Interestingly, PPAR genes have coregulator recruitment. evolved 2–3 times faster
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