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

2022/01/03 by Calum Gabbutt, Ryan O. Schenck, Daniel J. Weisenberger +14 · 1 voice · 3 citations
Biochemistry, Genetics and Molecular Biology · #Cancer Genomics and Diagnostics #Epigenetics and DNA Methylation #Genomics and Chromatin Dynamics

paper · pdf · doi:10.1038/s41587-021-01109-w

openalex publication_date 2022/01/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31

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).

Citations

• Inference from Iterative Simulation Using Multiple Sequences
• Programming of DNA Methylation Patterns
• Rank-Normalization, Folding, and Localization: An Improved Rˆ for Assessing Convergence of MCMC (with Discussion)
• dynesty: a dynamic nested sampling package for estimating Bayesian posteriors and evidences
• Cancer Statistics, 2021

Cited by

• Evolutionary dynamics of 1,976 lymphoid malignancies predict clinical outcome
• Detecting and quantifying clonal selection in somatic stem cells
• Charting single-cell lineages with synthetic and natural barcodes

Discussions

• Evolution is a dynamic process, but often clinicians only have a single snapshot of a tumour. In our paper last year, we discovered fluctuating methylation as a natural “evolving barcode”, which encod [bsky, 1 points, 1 comments]

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