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.
|Advisor:||Telese, Francesca, Rosenfeld, Michael G.|
|Commitee:||Bloodgood, Brenda, Kadonaga, James|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||MAI 57/02M(E), Masters Abstracts International|
|Subjects:||Molecular biology, Neurosciences|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be