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

ABSTRACT: Transcriptome analysis of nucleus accumbens shell samples from RARβ-null mutant mice and their wild type littermates 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. We analyzed nucleus accumbens from 11 mice (6 WT, 5 RARβ-null mutant mice) using the Affymetrix GeneChip Mouse Gene 1.0 ST arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Doulaye Dembele 

PROVIDER: E-GEOD-67761 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress