| First Author | Niewiadomska-Cimicka A | Year | 2017 |
| Journal | Mol Neurobiol | Volume | 54 |
| Issue | 5 | Pages | 3859-3878 |
| PubMed ID | 27405468 | Mgi Jnum | J:274711 |
| Mgi Id | MGI:6294003 | Doi | 10.1007/s12035-016-0010-4 |
| Citation | Niewiadomska-Cimicka A, et al. (2017) Genome-wide Analysis of RARbeta Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders. Mol Neurobiol 54(5):3859-3878 |
| abstractText | 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 RARbeta-null mutant mice, we identified genomic targets of RARbeta in the striatum. Characterization of RARbeta 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 RARbeta 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 RARbeta 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 RARbeta 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 RARbeta in huntingtin protein aggregates may account for reduced RA signaling reported in HD. |
