title: Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.
abstract: Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e-5), cAMP (p = 4.5e-4), and calcium signaling (p = 3.4e-3). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Niewiadomska-Cimicka
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.|MRC Laboratory of Molecular Biology, Francis Crick Avenue, CB2 0QH, Cambridge, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krzyżosiak
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Podleśny-Drabiniok
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France.|Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France. krezel@igbmc.fr.|Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France. krezel@igbmc.fr.|Institut National de la Santé et de la Recherche Médicale, U 964, Illkirch, France. krezel@igbmc.fr.|Université de Strasbourg, Illkirch, France. krezel@igbmc.fr.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France. krezel@igbmc.fr.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krężel
mesh_terms: D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D055106:Genome-Wide Association Study; D000071058:Huntingtin Protein / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D066329:Protein Aggregates; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015203:Reproducibility of Results; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D000071058:Huntingtin Protein; D066329:Protein Aggregates; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin; D004247:DNA
keywords: ChIP-seq; Huntington’s disease; Nucleus accumbens; RAR; Response elements; Retinoic acid; Striatum; Transcriptome