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Inferring human stem cell behaviour from epigenetic drift.

ABSTRACT: Although conventional experimental manipulations are impractical, it may be possible to infer human stem cell fates by 'reading' histories recorded within their genomes. Genomes are almost perfect copies of copies, and ancestries may be surreptitiously recorded by replication errors that inevitably accumulate. The greater the number of divisions, the greater the number of replication errors ('a molecular clock hypothesis'). Mutations rarely occur during a lifetime, but DNA methylation patterns are also copied after DNA replication and measurably drift with ageing at certain CpG sites in mitotic tissues, such as the colon. Such passenger methylation pattern variation may effectively function as 'epigenetic' somatic cell mitotic clocks. Replication errors can only accumulate in long-lived stem cell lineages, so methylation pattern drift largely records stem cell behaviour. How methylation patterns may encode stem cell ancestries is illustrated with two types of small reproductive units--colon crypt niches with continuous genealogies, and hair follicles with punctuated genealogies. Potentially, the genealogy of any human cell may be inferred by 'reading' its genome.

SUBMITTER: Shibata D

PROVIDER: S-EPMC4156515 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Inferring human stem cell behaviour from epigenetic drift.

Shibata D D

The Journal of pathology 20090101 2

Although conventional experimental manipulations are impractical, it may be possible to infer human stem cell fates by 'reading' histories recorded within their genomes. Genomes are almost perfect copies of copies, and ancestries may be surreptitiously recorded by replication errors that inevitably accumulate. The greater the number of divisions, the greater the number of replication errors ('a molecular clock hypothesis'). Mutations rarely occur during a lifetime, but DNA methylation patterns a ...[more]

PMID: 19031430

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Project description:Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here, we identify and validate 781 CpG islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (?3-4-fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-to-carcinoma sojourn time distributions from colorectal cancer incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77% to 89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplastic progression, whereas only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of colorectal cancer. Methylomic drift advanced in colorectal neoplasia, consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in colorectal cancer. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence. SIGNIFICANCE: These findings present age-related methylomic drift in colorectal neoplasia as evidence that premalignant cells can persist for decades before becoming cancerous.See related commentary by Sapienza, p. 437.

Dataset Information

Inferring human stem cell behaviour from epigenetic drift.

Publications

Inferring human stem cell behaviour from epigenetic drift.

Similar Datasets

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