Estrogen-related receptor gamma modulates energy metabolism target genes in human trophoblast D. Poidatz, E. Dos Santos, A. Brulé, P. De Mazancourt, M.N. Dieudonné * Université de Versailles-St Quentin, Service de Biochimie et Biologie Moléculaire, UPRES-EA 2493, Faculté de Médecine Paris-Ile de France Ouest, PRES Université Paris Grand Ouest (UPGO), Centre Hospitalier de Poissy-Saint Germain, 78303 Poissy Cedex, France article info Article history: Accepted 7 June 2012 Keywords: ERRg Human trophoblasts Energy metabolism abstract Placenta growth and functions depend on correct trophoblast migration, proliferation, and differentia- tion. The placenta has a critical role in gas and nutrient transport. To accomplish these numerous functions, the placenta depends on a highly efficient energy metabolism control. Recent studies showed that the orphan nuclear receptor Estrogen-Related Receptor gamma (ERRg) is highly expressed in human placentas. As ERRg has been described as a major energy metabolism regulator, we investigated ERRg expression and putative roles on energy homeostasis in human trophoblast from first trimester placentas. First, we showed that ERRg expression level increased during pregnancy and that ERRg was more abundant in villous than in extravillous trophoblasts. We also observed that ERRg expression increased during trophoblast differentiation. Second, we demonstrated that mitochondrial biogenesis and expression of some energy metabolism target genes decreased when ERRg expression was impaired. Altogether, these results suggest that ERRg could be implicated in the energy metabolism regulation of human trophoblasts. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The Estrogen-Related Receptors (ERRa, ERRb, and ERRg) are orphan nuclear receptors that were identified through their homology to the estrogen receptors. Despite this similarity, ERRs are not activated by estrogen. Indeed, the transcriptional activity of ERRs is constitutive and independent of exogenously added ligands [1]. Nevertheless, ERRs exhibit limited affinities for a variety of phar- macological molecules (diethylstilbestrol, 4-hydroxytamoxifen, DY131, Bisphenol A) [2e5]. The three ERRs recognize a common DNA sequence, termed ERR response element (ERRE), and act as transcription factors for genes bearing functional ERREs [6]. The transcriptional activity of ERRs is highly dependent on the presence of coactivator proteins, most notably the peroxisome proliferator-activated receptor g coac- tivators-1a and -1b (PGC-1a and PGC-1b) [7,8]. The ERRs can also interact with e and be stimulated by -some members of the steroid receptor coactivator (SRC) family [9,10]. On the other hand, the transcriptional activity of ERRs can be suppressed by the nuclear receptor interacting protein-140 (RIP-140) or by the orphan nuclear receptor small heterodimer partner (SHP) [11,12]. Therefore, the relative levels of specific coactivator and corepressor proteins present in a given cell type dictate whether the ERRs act as activators or repressors of gene expression in this given tissue or cell line. Biological functions of the different ERR were partly unravelled using in vivo models. ERRa-knockout mice are viable but exhibit reduced body weight and peripheral fat deposits [13]. These effects were attributed to the regulation of energy metabolism by ERRa. ERRb plays a major role in mice placental development resulting in early lethality of ERRbnull embryos [14]. Concerning ERRg, null mice die shortly after birth due to cardiac deficiency and impaired mitochondrial functions [15]. While these three ERRs seem to exert tissue-specific effects, all three are expressed at high levels in tissues with elevated metabolic demands, such as the heart, kidney, and skeletal muscles [16e18]. ERRs can be viewed as energy sensors put at stake under various stress and energy requirements. Functional genomics studies demonstrated that ERRs are key Abbreviations: ERRg, estrogen related receptor gamma; RT-PCR, reverse transcription-polymerase chain reaction; PGC-1a, PPARg coactivator-1a; PDK4, pyruvate deshydrogenase kinase 4; PPARg, peroxisome proliferator activated receptor-g; MCAD, medium chain acyl-coA Deshydrogenase; TBP, TATA box binding protein; RPL13A, ribosomal protein L13a; VCT, villous cytotrophoblast; EVCT, extra villous cytotrophoblast. * Corresponding author. Service de Biologie Médicale, Centre Hospitalier, 78303 Poissy Cedex, France. Tel.: þ33 139275465; fax: þ33 139275466. E-mail addresses: biochip@wanadoo.fr, marie-noelle.dieudonne@uvsq.fr (M.N. Dieudonné). Contents lists available at SciVerse ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta 0143-4004/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.placenta.2012.06.002 Placenta 33 (2012) 688e695