Global analysis of drug-regulated alternative expression of genes in mouse brain

Genomic response of neuronal cell to external stimuli includes expression of specific transcript isoforms, that use alternative transcription start sites and polyadenylation signals. We applied microarray profiling (Illumina Mouse WG-6) and next-generation sequencing (SOLID 5500xl) to screen for drug-induced activitydependent transcriptional events in the C57BL/6J mouse striatum. We compared effects on gene expression induced by psychoactive drugs with diverse neuropharmacological mechanisms of action (antidepressants, antipsychotics, anxiolytics, psychostimulants and opiods). Using whole-genome approach we identified a pool of transcripts that are regulated by the psychotropic drugs in mouse striatum (317 transcripts). We found that drug-responsive transcripts are organized into three main co-regulated gene expression networks. Furthermore, using Bowtie read aligner and Cufflinks algorithm we identified specific gene isoforms responsive to drug treatment. 58% among the drug-regulated transcripts were defined as alternative transcription events. To search for transcriptional factors that control alternative gene transcription in the brain we developed seqinterpreter web-based tool (http:// seqinterpreter.cremag.org). We found SRF, NPAS4 and GR as candidate regulatory factors. The complex program of regulation in gene transcription may further impact long-lasting alterations in brain function.