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Genome-wide analysis of RARβ transcriptional targets in mouse striatum links retinoic acid signaling with Huntington’s disease and other neurodegenerative disorders

ABSTRACT: The active vitamin A derivative retinoic acid (RA) is an important regulator of adult brain functions. How these regulations are achieved is poorly known, partly due to the paucity of information on RA molecular targets. The striatum, the region involved in control of motor, cognitive and affective functions, may be particularly prone to such regulation as it displays the highest levels of RA and its receptors (RARs). We report the first genome-wide analysis of RAR-binding sites in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), as well as transcriptomic analysis of RARβ-null mutant mice, we identified genomic transcriptional targets of RARβ in the striatum. Our data point to a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein, cAMP and calcium signaling. Quantitative PCR analysis of striatal subregions revealed a higher sensitivity of ventral structures (nucleus accumbens) to lack of RARβ signaling. There is a high overlap of transcriptional targets of RARβ and genes affected in expression in Huntington’s disease (HD), and we observed a decrease of RARβ expression in the striatum of R6/2 transgenic mice, a murine model of HD. A large number of genes bearing RARβ binding sites have also been implicated in Alzheimer’s and Parkinson’s diseases, raising the possibility that compromised RA signaling in striatum may be a mechanistic link explaining the similar affective and cognitive symptoms of these diseases. Globally, our data point to a possibility of a neuroprotective function of RARβ in the striatum. Genome-wide mapping of RARβ and H3K4me3 binding sites in mouse caudate putamen

ORGANISM(S): Mus musculus  

SUBMITTER: Wojciech Krezel   Tao Ye  Tao YE  Anna Niewiadomska-Cimicka 

PROVIDER: E-GEOD-67829 | ArrayExpress | 2016-07-22



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Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.

Niewiadomska-Cimicka Anna A   Krzyżosiak Agnieszka A   Ye Tao T   Podleśny-Drabiniok Anna A   Dembélé Doulaye D   Dollé Pascal P   Krężel Wojciech W  

Molecular neurobiology 20160712 5

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 tra  ...[more]

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