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The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

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Posteriors of N and g in Models with Short Niche Succession TimeThree models that assume a niche succession time of about one year (τ = 1) are compared: same model as before but with τ = 1 (plain line); τ = 1 and high level of methylation/demethylation during cell differentiation (α > 0.1, dashed line); τ = 1, α > 0.1, without imposing a star-like genealogy for differentiation lineages (0 < g < 10, dotted line).
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pcbi-0030028-g008: Posteriors of N and g in Models with Short Niche Succession TimeThree models that assume a niche succession time of about one year (τ = 1) are compared: same model as before but with τ = 1 (plain line); τ = 1 and high level of methylation/demethylation during cell differentiation (α > 0.1, dashed line); τ = 1, α > 0.1, without imposing a star-like genealogy for differentiation lineages (0 < g < 10, dotted line).

Mentions: The model and its associated inference procedure provide an invaluable tool to further explore the hypothesis of a high amount of pattern changes during cell differentiation. A relatively high value of α is particularly realistic in a scenario with short niche succession time (small τ). As an illustration, we investigate here what could be the consequence of a niche succession time of about one year (τ = 1). We can see in Figure 8 that setting the parameter τ to 1 has no impact on the posterior of N. We also found that the constraint τ = 1 has no impact on the estimate of α (unpublished data) and g (Figure 8, right panel). From a biological point of view, however, a short niche succession time does not seem compatible with a very small value of α. Indeed, a τ of one year suggests that niche succession may be reached after only 50 cell cycles, compared with a minimum of five cell cycles for cell differentiation. We thus expect α greater than 0.1 = 5/50. The posterior of N was therefore investigated subject to this constraint. Results are presented in Figure 8 and reveal the deep impact of such a high value of α on the posterior of N, which now indicates a value of N between four and 12, whereas the value of g is close to five.


The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Posteriors of N and g in Models with Short Niche Succession TimeThree models that assume a niche succession time of about one year (τ = 1) are compared: same model as before but with τ = 1 (plain line); τ = 1 and high level of methylation/demethylation during cell differentiation (α > 0.1, dashed line); τ = 1, α > 0.1, without imposing a star-like genealogy for differentiation lineages (0 < g < 10, dotted line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808490&req=5

pcbi-0030028-g008: Posteriors of N and g in Models with Short Niche Succession TimeThree models that assume a niche succession time of about one year (τ = 1) are compared: same model as before but with τ = 1 (plain line); τ = 1 and high level of methylation/demethylation during cell differentiation (α > 0.1, dashed line); τ = 1, α > 0.1, without imposing a star-like genealogy for differentiation lineages (0 < g < 10, dotted line).
Mentions: The model and its associated inference procedure provide an invaluable tool to further explore the hypothesis of a high amount of pattern changes during cell differentiation. A relatively high value of α is particularly realistic in a scenario with short niche succession time (small τ). As an illustration, we investigate here what could be the consequence of a niche succession time of about one year (τ = 1). We can see in Figure 8 that setting the parameter τ to 1 has no impact on the posterior of N. We also found that the constraint τ = 1 has no impact on the estimate of α (unpublished data) and g (Figure 8, right panel). From a biological point of view, however, a short niche succession time does not seem compatible with a very small value of α. Indeed, a τ of one year suggests that niche succession may be reached after only 50 cell cycles, compared with a minimum of five cell cycles for cell differentiation. We thus expect α greater than 0.1 = 5/50. The posterior of N was therefore investigated subject to this constraint. Results are presented in Figure 8 and reveal the deep impact of such a high value of α on the posterior of N, which now indicates a value of N between four and 12, whereas the value of g is close to five.

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

Show MeSH