John O’Neill

Cellular rhythms, signalling and metabolic regulation

oneillj@mrc-lmb.cam.ac.uk
Personal group site

Most organisms display ~24-hour cycles in their biology. In humans and other animals, these circadian rhythms result from daily timing mechanisms in every cell that together function like a biological clock; allowing our physiology to anticipate and prepare for the differing demands of day and night. Normally our biological clock is fine-tuned each day by the schedule we keep, particularly the timing of meals and light exposure. When we see bright light or eat at the wrong biological time, as often occurs during shift work or jet-lag, it disrupts our biological clock and increases the risk of chronic illnesses such as type II diabetes, cardiovascular disease and some cancers. Conversely, the effectiveness of some drugs and surgeries can vary with the biological time of treatment. Delineating the molecular mechanisms that impart daily rhythms to our biology is therefore important for understanding human health and may provide new insights into the prevention and treatment of many diseases.

Cellular clocks drive daily rhythms of clock gene activity that persist for many days, in isolated skin cells for example

Wounds that happen during the active phase of the circadian cycle heal more rapidly because cells are quicker to migrate and repair the damage (Hoyle *et al* 2017, Science Translational Medicine)

Our current research is focused on understanding the fundamental mechanisms of daily cellular timekeeping and how circadian regulation of biological function is achieved. To achieve these goals we employ a wide range of molecular biology, proteomic, metabolomic and biochemical techniques, supported by real-time fluorescent and bioluminescent reporters.

Schematic — Circadian rhythms in cellular function are synchronised by extracellular timing cues and facilitated by daily cycles in the activity of transcription factors encoded by clock genes, such as Period1, 2 & 3. Clock proteins auto-repress via transcription-translation feedback loops (TTFL), whereas their translation, activity and stability are regulated post-translationally.

Recently we found that post-prandial increases in insulin signaling synchronise circadian rhythms throughout the body with feeding time, by increasing the production of PER clock proteins (Crosby et al 2019, Cell).

Selected Papers

Rzechorzek, N.M., Thrippleton, M.J., Chappell, F.M., Mair, G., Ercole, A., Cabeleira, M., The CENTER-TBI High Resolution ICU (HR ICU) Sub-Study Participants and Investigators, Rhodes, J., Marshall, I., and O’Neill, J.S. (2022)
A daily temperature rhythm in the human brain predicts survival after brain injury.
Brain 00: 1-18
Stangherlin, A., Watson, J.L., Wong, D.C.S., Barbiero, S., Zeng, A., Seinkmane, E., Peak Chew, S., Beale, A.D., Hayter, E.A., Guna, A., Inglis, A.J., Putker, M., Bartolami, E., Matile, S., Lequeux, N., Pons, T., Day, J., van Ooijen, G., Voorhees, R.M., Bechtold, D.A., Derivery, E., Edgar, R.S., Newham, P., O’Neill, J.S. (2021)
Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology
Nature Communications 12(1): 6035
Putker M., Wong D. C. S., Seinkmane E., Rzechorzek N. M., Zeng A., Hoyle N. P., Chesham J. E., Edwards M. D., Feeney K. A., Fischer R., Peschel N., Chen K. F., Vanden Oever M., Edgar R. S., Selby C. P., Sancar A., O'Neill J. S. (2021)
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping
EMBO J. 40(7): e106745.
Crosby, P., Hamnett, R., Putker, M., Hoyle, N.P., Reed, M., Karam, K.J., Maywood, E.S., Stangherlin, A., Chesham, J.E., Hayter, E.A., Rosenbrier-Ribeiro, L., Newham, P., Clevers, H., Bechtold, D.A., O’Neill, J.S. (2019)
Insulin/IGF-1 drives PERIOD synthesis to entrain circadian rhythms with feeding time.
Cell 177(4): 896-909.
Hoyle, N. P., Seinkmane, E., Putker, M., Feeney, K. A., Krogager, T. P., Chesham, J. E., Bray, L. K., Thomas, J. M., Dunn, K., Blaikley, J. & O'Neill, J. S. (2017)
Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing.
Science Translational Medicine 9(415): pii: eaal2774.
Feeney K. A., Hansen L. L., Putker M., Olivares-Yañez C., Day J., Eades L. J., Larrondo L. F., Hoyle N. P., O'Neill J. S., van Ooijen G (2016)
Daily magnesium fluxes regulate cellular timekeeping and energy balance
Nature 532(7599): 375-379.
O'Neill, J.S., van Ooijen, G., Dixon, L.E., Troein, C., Corellou, F., Bouget, F.Y., Reddy, A.B. and Millar, A.J. (2011)
Circadian rhythms persist without transcription in a eukaryote.
Nature 469: 554-558.
O'Neill, J.S. and Reddy, A.B. (2011)
Circadian clocks in human red blood cells.
Nature 469: 498-503.

Group Members

Andrew Beale
Anna Edmondson
Nathan James
Andrei Mihut
Jack Munns
Nina Rzechorzek
Estere Seinkmane
Aiwei Zeng