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: We next explored the relationship of LBR, LMNB1, and MAN1 by examining mRNA and protein levels while knocking them down one at a time. Both LBR and LMNB1 knockdown significantly decreased the transcript level of MAN1 (by 15% and 40%, respectively) (Figure 3A). The effects of LBR or LMNB1 knockdown on MAN1 expression are even more dramatic at the protein level, with 54% and 44% reductions, respectively (Figure 3B). Moreover, knockdown of LBR expression reduces the amount of LMNB1 protein by 32%, which is consistent with the observation that reduction of LBR expression in the fibroblasts of patients harboring a heterozygous LBR mutation results in the abolition of LMNB1 protein (Gaudy-Marqueste et al., 2010), whereas a decrease in LMNB1 does not significantly affect LBR expression. MAN1 knockdown also does not change the expression of LBR and LMNB1, either at the mRNA or protein level (Figure 3). These results suggest that MAN1 is modulated by LBR and LMNB1, and thus the effects of LBR and LMNB1 on the clock are at least partially through MAN1. Therefore, we further investigated the effects of MAN1 on the molecular clock.10.7554/eLife.02981.010Figure 3.Knocking down LBR/LMNB1 reduces MAN1 mRNA and protein levels but not vice versa.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.