Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks

Gabbutt, C.; Schenck, R. O.; Weisenberger, D.; Kimberley, C.; Berner, A.; Househam, J.; Lakatos, E.; Robertson-Tessi, M.; Martin, I.; Patel, R.; Clark, S.; Latchford, A.; Barnes, C. P.; Leedham, S. J.; Anderson, A. R.; Graham, T. A.; Shibata, D.

doi:10.1101/2021.03.15.435426

bioRxiv · 10.1101/2021.03.15.435426

Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks

Gabbutt, C.·Schenck, R. O.·Weisenberger, D.·Kimberley, C.·Berner, A.·Househam, J.·Lakatos, E.·Robertson-Tessi, M.·Martin, I.·Patel, R.·Clark, S.·Latchford, A.·Barnes, C. P.·Leedham, S. J.·Anderson, A. R.·Graham, T. A.·Shibata, D.

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Abstract

Molecular clocks record cellular ancestry. However, currently used clocks tick too slowly to measure the short-timescale dynamics of cellular renewal in adult tissues. Here we develop rapidly oscillating DNA methylation clocks where ongoing (de)methylation causes the clock to tick-tock back-and-forth between methylated and unmethylated states like a pendulum. We identify oscillators using standard methylation arrays and develop a mathematical modelling framework to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than colon (6.5 {+/-} 1.0 vs 5.8 {+/-} 1.7 stem cells/crypt) with slower stem cell replacement in small intestine (0.79 {+/-} 0.5 vs 1.1 {+/-} 0.8 replacements/stem cell/year). Germline APC mutation increased the number of replacements per crypt (13.0 {+/-} 2.4 replacements/crypt/year vs 6.9 {+/-} 4.6 for healthy colon). In blood, we measure rapid expansion of acute leukaemia and slower growth of chronic disease. Rapidly oscillating molecular clocks are a new methodology to quantitatively measure human somatic cell dynamics.

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Gabbutt, C., Schenck, R. O., Weisenberger, D., Kimberley, C., Berner, A., Househam, J., Lakatos, E., Robertson-Tessi, M., Martin, I., Patel, R., Clark, S., Latchford, A., Barnes, C. P., Leedham, S. J., Anderson, A. R., Graham, T. A., Shibata, D.. 2021-03-16. Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks. https://doi.org/10.1101/2021.03.15.435426

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