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Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues

Gabbutt, C; Schenck, RO; Weisenberger, DJ; Kimberley, C; Berner, A; Househam, J; Lakatos, E; ... Shibata, D; + view all (2022) Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues. Nature Biotechnology 10.1038/s41587-021-01109-w. (In press). Green open access

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Abstract

Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).

Type: Article
Title: Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41587-021-01109-w
Publisher version: https://doi.org/10.1038/s41587-021-01109-w
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biotechnology & Applied Microbiology, MITOCHONDRIAL-DNA MUTATIONS, STEM-CELL, HUMAN COLON, INTESTINAL EPITHELIUM, FIELD CANCERIZATION, CLONAL ARCHITECTURE, SOMATIC MUTATIONS, GENE-EXPRESSION, CRYPT, REVEALS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10141745
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