Translation control of circadian rhythms

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K14755
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44050:Animal physiological chemistry, physiology and behavioral biology-related
• Research Institution: Osaka University (2019-2020); Institute of Physical and Chemical Research (2018)
• Principal Investigator: Millius Arthur 大阪大学, 免疫学フロンティア研究センター, 特任研究員(常勤) (80624858)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Ribosome profiling / Circadian rhythms / Period2 / Translation / uORF / RNA structure / Sleep

Outline of Final Research Achievements

We used a method called ribosome profiling to understand RNA translation in mice liver over a 24-h period, and compared these results to RNA and protein levels for select circadian genes. We discovered that upstream open reading frames (uORFs) in some mRNAs suppress the degree of ribosome binding in the downstream coding region. We explored how the number and length of uORFs affect their degree of downstream repression and examined uORF repression in individual cells. We mutated the uORF in a central circadian gene Period2 and found that both male and female mutant mice had significantly reduced sleep compared to their wild-type littermates. Thus, our research suggests that circadian control of RNA translation can physiologically alter mice behavior and has implications for developing the next generation of RNA therapeutics.

Free Research Field

Biology at cellular to organismal levels

Academic Significance and Societal Importance of the Research Achievements

Defects in circadian rhythms are related to health issues, such as obesity and depression, and understanding how translation is regulated is important for developing new treatments. Our results suggest that non-coding RNA structures alter translation, which has physiological consequences on sleep.