UC San Diego

Nuclear receptor co-repressors NCoR and SMRT are transcriptional regulatory proteins that interact with different transcription factors and epigenetic modifiers. Here, we study how NCoR/SMRT co-repressor complex regulates neuronal gene expression. In the lab, conditional knock-out mice have been developed to delete the NCoR and SMRT genes specifically in excitatory neurons of the postnatal forebrain. The conditional deletion of these genes is necessary because the traditional null mice die during embryonic development. Preliminary behavioral data show that the genetic deletion of both genes leads to stress-related behaviors. Hence, we hypothesize that NCoR/SMRT complex regulates the genomic action of glucocorticoid receptor (GR), a nuclear hormone receptor that functions as a cellular sensor for stress and it is known to interact with the NCoR/SMRT complex. To identify GR target genes regulated by NCoR/SMRT complex in the brain, we used NCoR/SMRT double knock-out mice and a transcriptomic approach known as Global Run-On sequencing. Subsequent bioinformatics analysis of sequencing data showed that the expression of hundreds of genes is altered upon genetic deletion of NCoR and SMRT. Moreover, biological processes linked to glucocorticoid signaling, such as immune response and circadian rhythm, were found to be dysregulated in the absence of NCoR and SMRT. These results provide evidence that NCoR/SMRT complex mediates the transcriptional regulation of key molecular pathways linked to the function of glucocorticoids in the brain.