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RAR/RXR Binding Dynamics Distinguish RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements Amandine Chatagnon, Philippe Veber, Valérie Morin, Justin Bedö„ Gérard Triqueneaux, Marie Sémon, Vincent Laudet, Florence d’Alché-Buc, Gérard Benoît, To cite this version: Amandine Chatagnon, Philippe Veber, Valérie Morin, Justin Bedö„ Gérard Triqueneaux, et al.. RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis- regulatory elements. Nucleic Acids Research, Oxford University Press, 2015, 43 (10), pp.4833–4854. 10.1093/nar/gkv370. hal-01170316 HAL Id: hal-01170316 https://hal.archives-ouvertes.fr/hal-01170316 Submitted on 27 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial| 4.0 International License Published online 20 April 2015 Nucleic Acids Research, 2015, Vol. 43, No. 10 4833–4854 doi: 10.1093/nar/gkv370 RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements Amandine Chatagnon1,†, Philippe Veber2,†,Valerie´ Morin1, Justin Bedo3, Gerard´ Triqueneaux1,MarieSemon´ 4, Vincent Laudet4, Florence d’Alche-Buc´ 3 and Gerard´ Benoit1,* 1Universite´ de Lyon, Universite´ Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France, 2Universite´ de Lyon, Universite´ Claude Bernard Lyon1, LBBE UMR CNRS 5558, 69622 Villeurbanne, France, 3Universite´ d’Evry-Val d’Essonne, IBISC EA 4526, 91037 Evry, France and 4IGFL, Universite´ de Lyon, Universite´ Lyon 1, CNRS, INRA; Ecole Normale Superieure´ de Lyon, 69007 Lyon, France Received August 11, 2014; Revised March 09, 2015; Accepted April 08, 2015 ABSTRACT INTRODUCTION In mouse embryonic cells, ligand-activated retinoic Retinoic acid (RA), the main active vitamin A metabolite, acid receptors (RARs) play a key role in inhibiting is a well-known regulator of embryonic development as well pluripotency-maintaining genes and activating some as adult physiology (1). The highly pleiotropic organismal major actors of cell differentiation. and cellular effects of RA are mainly mediated by the com- To investigate the mechanism underlying this dual binatorial action of six nuclear receptors [retinoic acid re- ceptors NR1B (RARA, RARB and RARG) and retinoid regulation, we performed joint RAR/RXR ChIP-seq X receptors NR2B (RXRA, RXRB and RXRG)], which and mRNA-seq time series during the first 48 h of form heterodimers and act as RA-modulated transcription the RA-induced Primitive Endoderm (PrE) differenti- factors. ation process in F9 embryonal carcinoma (EC) cells. At the cellular level, RA stimulation triggers fundamen- We show here that this dual regulation is associated tal biological processes, such as growth arrest, differenti- with RAR/RXR genomic redistribution during the dif- ation and apoptosis. Long before the elucidation of the ferentiation process. In-depth analysis of RAR/RXR molecular mechanisms supporting their action, retinoids binding sites occupancy dynamics and composition have been recognized as mediators of cell differentiation show that in undifferentiated cells, RAR/RXR inter- both in vivo and in vitro (2–5). Among the various RA sen- act with genomic regions characterized by binding of sitive tissues and cell types, embryonal carcinoma (EC) and pluripotency-associated factors and high prevalence later, embryonic stem (ES) cells were shown to undergo dif- ferentiation upon RA stimulation (6). This ever since re- of the non-canonical DR0-containing RA response el- / mained the treatment of choice to induce in vitro differ- ement. By contrast, in differentiated cells, RAR RXR entiation of mouse and human ES cells. ES and EC cells bound regions are enriched in functional Sox17 bind- are characterized by their self-renewal capacity as well as ing sites and are characterized with a higher fre- their ability to differentiate into various cell lineages, thus quency of the canonical DR5 motif. Our data offer providing invaluable biological models to study early devel- an unprecedentedly detailed view on the action of opmental processes. Molecular regulators of pluripotency RA in triggering pluripotent cell differentiation and and self-renewal maintenance have been gradually eluci- demonstrate that RAR/RXR action is mediated via dated and rely on a core transcription factor triumvirate two different sets of regulatory regions tightly asso- composed of SOX2, NANOG and POU5F1 that acts in ciated with cell differentiation status. a concerted manner to maintain a proliferating and un- differentiated state while preventing lineage specific differ- entiation (7). Importantly, the elucidation of pluripotency *To whom correspondence should be addressed. Tel: +33 4 72 44 80 41; Fax: +33 4 72 43 26 85; Email: [email protected] †These authors contributed equally to the paper as first authors. Present address: Amandine Chatagnon, Plateforme de Biologie Moleculaire,´ IBP, CHU Grenoble, 38043 Grenoble, France. Former address: Amandine Chatagnon, Philippe Veber, Gerard´ Triqueneaux, and Gerard´ Benoit, IGFL, Universite´ de Lyon, Universite´ Lyon 1, CNRS, INRA; Ecole Normale Superieure´ de Lyon, 69007 Lyon, France. C The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 4834 Nucleic Acids Research, 2015, Vol. 43, No. 10 mechanisms provided molecular basis for somatic cells re- DR0-bound RAR/RXR dimers do not modulate gene ex- programming into ES-like cells also referred to as induced pression in reporter in vitro assay (25). Noticeably, by con- pluripotent stem cells (iPSc), by the ectopic overexpression trast with a previous report which identified the DR5 motif of defined transcription factors (8). More recently, addi- as the most prevalent motif in RAR/RXR occupied DNA tional regulators of gene expression were shown to collabo- regions in MCF7 cells (21), the DR0 motif was found as the rate with POU5F1, SOX2 and NANOG to control the ESc most significantly enriched hormone response element in gene expression program and/or to improve somatic cells RAR/RXR targeted regions in mES/mEC cells (25), thus reprogramming. These factors exert various transcription- suggesting that the recruitment of RAR/RXR on genomic related function ranging from transcriptional factors (e.g. loci encompassing a DR0 motif is favored in pluripotent MYC, MYCN, KLF4, STAT3, SMAD1, TCF3) and co- embryonic cells. factors (e.g. EP300, Mediator complex subunits) to chro- These observations prompted us to hypothesize that the matin modifiers (e.g. PcG). Interestingly, several nuclear re- differentiation process is coupled with a drastic reorga- ceptors emerged as important players in the maintenance of nization of the RAR/RXR binding repertoire. To get a pluripotency and somatic cell reprogramming (i.e. ESRRB, clear picture of this change and of its transcriptional con- NR5A1, NR5A2, NR0B1) as well as in pluripotent cell sequences, we performed a time-course analysis of whole- differentiation induction (i.e. NR2F1, NR2F2, NR6A1). genome RAR/RXR binding as well as global gene expres- Paradoxically, RA-activated RARG was also shown to be sion profiling, in RA-induced differentiating F9 embryonal involved in promoting somatic cell reprogramming toward carcinoma cells. iPSc (9), in contradiction with its well-documented in vitro Our study highlights the dynamic binding pattern of differentiating effect of ES/EC cells. RAR/RXR during the differentiation process and the di- The nuclear hormone receptor family consists of 48/49 versity and composite nature of recognized DNA motifs. (human/mouse) evolutionary-conserved ligand-dependent We establish that the dynamic occupation patterns observed transcription factors sharing important structural and result from multiple mechanisms associated with (i) the abil- functional features. As such, they are characterized by the ity of RAR/RXR heterodimers to interact with DNA, and presence of two conserved domains, the central DNA bind- (ii) region-specific features (e.g. RARE motif, specific tran- ing domain (DBD) which interacts with the core motif 5- scription factor binding and DNA accessibility). By com- RGKTSA-3 (10–12), and the C-terminal ligand-binding bining these results with gene expression data, we iden- domain (LBD) which largely determines nuclear receptor tified dynamical transcriptional patterns that can be reli- dimerization properties (13). Monomeric NRs recognize ably associated with specific cis-regulatory events includ- a single core motif, while dimeric NR complexes interact ing RAR/RXR binding dynamics. Altogether, our results with repeated occurrences of this core motif. The spacer enable us to propose an integrated model
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