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: In order to investigate whether NE proteins are involved in circadian regulation, we began by focusing on lamin B1 since it has been shown to play a role in transcriptional regulation (Hutchison, 2002; Shevelyov et al., 2009). In vivo oscillation of lamin B1 (Lmnb1) expression patterns (both RNA and protein levels) were confirmed using mouse tissues from suprachiasmatic nuclei (SCN), kidney, and liver (Figure 1A,B). To test whether the level of lamin B1 affects the molecular clock, we examined the protein expression patterns for the core clock gene PERIOD2 (PER2) using Lmnb1 heterozygous knock out (homozygosity is lethal) and LMNB1 wild-type BAC transgenic mice (Vergnes et al., 2004; Heng et al., 2013). Oscillating PER2 expression patterns were phase delayed in Lmnb1 heterozygous knock out mice and phase advanced in LMNB1 BAC transgenic mice (overexpression) when compared to wild-type control mice (Figure 1C), suggesting that the level of lamin B1 can modulate circadian clock. However, neither Lmnb1 heterozygous knock out mice nor LMNB1 BAC transgenic mice demonstrated significant output behavioral change (Figure 1—figure supplement 1). To expand the investigation, we chose to include two additional NE proteins that are known to associate with lamin B1, LBR, and MAN1. We found that LBR and MAN1 expression also oscillate, albeit mildly for MAN1 (Figure 1D).10.7554/eLife.02981.003Figure 1.Lamin b1 regulates the circadian clock.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.