Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/17/2008
Publication Date: 5/17/2008
Citation: Montemayor, C., Ruiz, F.R., Young, M.E., Pereira, F.A. 2008. Bmal1 is a direct transcriptional target of the orphan nuclear receptor, NR2F1 [abstract]. Proceeding,Society for Research on Biological Rhythms. May 17-21, 2008, San Delia, Florida. p. 64. Interpretive Summary:
Technical Abstract: Orphan nuclear receptor NR2F1 (also known as COUP-TFI, Chicken Ovalbumin Upstream Promoter Transcription Factor I) is a highly conserved member of the nuclear receptor superfamily. NR2F1 plays a critical role during embryonic development, particularly in the central and peripheral nervous systems and in the inner ear. In the mouse cochlea, NR2F1 controls Notch signaling to regulate precursor cell differentiation into hair cells and supporting cells. In order to further identify pathways downstream of NR2F1, we obtained microarray gene expression profiles from wild type and Nr2f1–/– inner ear tissues. One of the most significant expression changes, as validated by real-time RT-PCR, is the core circadian gene Period1. Indeed, over-expressing NR2F1 in cells in culture resulted in complete deregulation of the circadian clock mechanism. We next performed chromatin immunoprecipitation (CHiP) and promoter-luciferase reporter assays and determined that NR2FI directly occupies the Bmal1 promoter and activates its transcription rate. Furthermore, nr2f1 transcript levels oscillate in a circadian manner in mouse embryonic fibroblasts (MEFs) and in NIH3T3 cells synchronized by serum-shock. Importantly, the Bmal1 transcript response to serum shock is altered in NR2F1–/– MEFs when compared to wild type controls. These results implicate NR2F1 in regulating both the circadian and Notch cyclic networks during inner ear development.