| First Author | Takeda Y | Year | 2012 |
| Journal | Nucleic Acids Res | Volume | 40 |
| Issue | 17 | Pages | 8519-35 |
| PubMed ID | 22753030 | Mgi Jnum | J:199687 |
| Mgi Id | MGI:5504349 | Doi | 10.1093/nar/gks630 |
| Citation | Takeda Y, et al. (2012) RORgamma directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res 40(17):8519-35 |
| abstractText | In this study, we demonstrate that the lack of retinoic acid-related orphan receptor (ROR) gamma or alpha expression in mice significantly reduced the peak expression level of Cry1, Bmal1, E4bp4, Rev-Erbalpha and Per2 in an ROR isotype- and tissue-selective manner without affecting the phase of their rhythmic expression. Analysis of RORgamma/RORalpha double knockout mice indicated that in certain tissues RORgamma and RORalpha exhibited a certain degree of redundancy in regulating clock gene expression. Reporter gene analysis showed that RORgamma was able to induce reporter gene activity through the RORE-containing regulatory regions of Cry1, Bmal1, Rev-Erbalpha and E4bp4. Co-expression of Rev-Erbalpha or addition of a novel ROR antagonist repressed this activation. ChIP-Seq and ChIP-Quantitative real-time polymerase chain reaction (QPCR) analysis demonstrated that in vivo RORgamma regulate these genes directly and in a Zeitgeber time (ZT)-dependent manner through these ROREs. This transcriptional activation by RORs was associated with changes in histone acetylation and chromatin accessibility. The rhythmic expression of RORgamma1 by clock proteins may lead to the rhythmic expression of RORgamma1 target genes. The presence of RORgamma binding sites and its down-regulation in RORgamma-/- liver suggest that the rhythmic expression of Avpr1a depends on RORgamma consistent with the concept that RORgamma1 provides a link between the clock machinery and its regulation of metabolic genes. |
