Genome-wide Analysis of RAR β Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington’s Disease and Other Neurodegenerative 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 RAR β-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 sig nificance (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 RAR β 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.
Source: Molecular Neurobiology - Category: Neurology Source Type: research