PT  - JOURNAL ARTICLE
AU  - Rebecca A. Mosig
AU  - Allison N. Castaneda
AU  - Jacob C. Deslauriers
AU  - Landon P. Frazier
AU  - Kevin L. He
AU  - Naseem Maghzian
AU  - Aarati Pokharel
AU  - Camille T. Schrier
AU  - Lily Zhu
AU  - Nobuya Koike
AU  - John J. Tyson
AU  - Carla B. Green
AU  - Joseph S. Takahashi
AU  - Shihoko Kojima
TI  - Natural Antisense Transcript of <em>Period2, Per2AS</em>, regulates the amplitude of the mouse circadian clock
AID  - 10.1101/2020.07.27.222760
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.27.222760
4099  - http://biorxiv.org/content/early/2020/07/28/2020.07.27.222760.short
4100  - http://biorxiv.org/content/early/2020/07/28/2020.07.27.222760.full
AB  - Circadian transcriptome studies identified a novel transcript at the Period2 (Per2) locus, which we named Per2AS. Per2AS is a long non-coding RNA transcribed from the antisense strand of Per2, and is expressed rhythmically and anti-phasic to Per2 mRNA. Previously, we mathematically tested the hypothesis that Per2AS and Per2 mutually inhibit each other’s expression by forming a double negative feedback loop, and found that Per2AS expands the oscillatory domain. In this study, we have experimentally tested this prediction by perturbing the expression of Per2AS in mouse fibroblasts. We found that Per2AS represses Per2 pre-transcriptionally in cis and regulates the amplitude of the circadian clock, but not period or phase. Unexpectedly, we also found that Per2 positively regulates Per2AS post-transcriptionally, indicating that Per2AS and Per2 form a single negative feedback loop. Because knock-down of Per2 does not recapitulate the phenotypes of Per2AS perturbation and Per2AS also activates Bmal1 in trans, we propose that Per2AS regulates the amplitude of the circadian clock without producing a protein by rewiring the molecular clock circuit.Competing Interest StatementThe authors have declared no competing interest.