Nuclear envelope protein MAN1 regulates clock through BMAL1.
Bottom Line: Our knowledge of these components and pathways is far from exhaustive.In recent decades, the nuclear envelope has emerged as a global gene regulatory machine, although its role in circadian regulation has not been explored.Our results establish a novel connection between the nuclear periphery and circadian rhythmicity, therefore bridging two global regulatory systems that modulate all aspects of bodily functions.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.Show MeSH
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Mentions: A lengthened period due to decreased MAN1 may arise from altered regulation of core clock proteins and/or altered transcription of core clock genes. Either of these effects would result in disruptions of the stoichiometry and temporal control of the dynamics of the core circadian feedback loops. Given what is known regarding the role of NE proteins in transcriptional regulation, we tested whether reductions in MAN1 expression would affect the transcription of clock genes. We examined the circadian oscillation of core clock genes at the mRNA level and found that only BMAL1 showed a clear difference wherein overall mRNA levels were down-regulated to half the levels of controls (Figure 4). Western blots also showed lower expression of BMAL1 when MAN1 was knocked down (Figure 4—figure supplement 1). The non-oscillatory CLOCK showed no significant change of either transcript or protein levels (Figure 4, Figure 4—figure supplement 1). The conserved mRNA levels of REV-ERBα and RORα in MAN1 knockdown cells suggest that the reduced BMAL1 expression is not caused by altered transcriptional activation of REV-ERBα, a BMAL1 repressor, or transcriptional repression of RORα, a BMAL1 activator.10.7554/eLife.02981.011Figure 4.Knocking down MAN1 reduces the levels of BMAL1 mRNA.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.