How is the amplitude of circadian rhythms regulated?
Our lab is interested in understanding how the mammalian circadian system sustains its robustness. Robustness is important to remain resilient against internal noise and external perturbations and not to lose rhythmicity, while flexibility offers the ability to synchronize to a new cycle (i.e., jet lag should not last forever).
One of the important factors that contributes to the robustness is the amplitude of circadian rhythms. Amplitude is an integral part of an oscillatory system, however, the regulatory mechanisms of amplitude remain largely unknown. Our lab wants to decipher how the amplitude of circadian rhythms is regulated. Because circadian clock is a complex system, we take an integrative approach and combine experimental, bioinformatical, and mathematical tools. We also take advantage of a molecular and cellular system to reduce the complexity of the system, although we plan to expand our analysis to tissue and organism levels in the future!
Amplitude of circadian rhythm changes in response to aging, feeding pattern, type of diet or other environmental factors, and amplitude abnormality is also known to have a negative impact on survival, fitness, and health of an organism. Disruptions of our internal clock are also implicated in many pathological states, including sleep and affective disorders, cardiovascular disease, and certain types of cancer. We live in a modern society where our internal clock is constantly abused by lifestyle and pathological factors, such as jet lag, artificial light, shift work, aging, depression, and Alzheimer’s diseases. All of our projects will not only provide fundamental biological insights how the amplitude and robustness of the circadian system is sustained, but also help design strategies and therapeutic interventions to improve our daily health and avoid health problems arising from disrupted circadian rhythms.
How can long non-coding RNAs regulate circadian rhythms without producing a protein!?
Recent genomic analyses revealed that the mammalian genome encodes at least as many non-coding RNAs (ncRNAs) as protein coding genes. These ncRNAs are also pervasively transcribed, and play important roles in disease development and a variety of biological processes, even though they were originally considered to be mere transcriptional noise and lack defined functions.
We recently identified a novel non-coding transcript, Per2AS, that appears to play an important role in the mammalian circadian clock system. Interestingly, both of our mathematical and experimental analyses demonstrated that Per2AS confers robustness to the system, and regulates the amplitude of circadian rhythms. We still do not know how Per2AS regulates robustness and amplitude without producing a protein, and we are working very hard to understand the mechanism how Per2AS, a non-coding RNA, regulates circadian rhythms.
What makes circadian rhythms in each organ different from each other?
Cell-autonomous circadian clocks drive thousands of rhythmic output genes that, ultimately, produce daily rhythms of many types of physiology and behavior. Interestingly, the number of cycling transcripts is vastly different among mouse tissues, despite the core molecular machinery (i.e., transcription-translation feedback loops) being nearly identical in all the tissues.
We are interested in understanding why some tissues are more robust and produce more cycling genes than others. To answer this, we bioinformatically characterized circadian transcriptome datasets in 12 mouse tissues and found that Rorc, one of the core clock genes, may be the key player to determine which tissues are more robust. We are currently using various experimental tools to validate our bioinformatical prediction and to understand how Rorc contributes to the robustness of the tissues.
Is RNA degradation important for high amplitude circadian gene expression?
For an mRNA to be rhythmically expressed, mRNA synthesis (i.e., transcription), degradation, or a combination of the two must be rhythmic, and the average degradation rate must be short enough (<10 hr). To achieve high amplitude, the amplitude of either RNA synthesis or degradation must be increased based on the mathematical prediction. Here, we aim to address three questions: (i) Which of the two processes (RNA synthesis or degradation) contributes most to the amplitude of rhythmic mRNA expression?, (ii) Is the coordination between rhythmic synthesis and degradation synergistic or additive to determine the amplitude of rhythmic mRNA expression, or do they cancel each other via transcription buffering and lead to low amplitude?, (iii) what is the trade-off of circadian mRNA expression with for high-amplitude? We are currently developing a new experimental tool to monitor the dynamics of rhythmic gene expression to answer these questions.