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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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Assessment of Model Fitness(Left) Model with independent sites. (Middle) Model with context-dependent methylation rate. (Right) Model with context-dependent methylation rate without data from patient X.Five within-crypt statistics are examined (in rows). For each of these statistics, the observed intercrypt average and standard deviation are plotted (vertical lines) along with their expected distribution given the posterior of the parameters. Statistics that fall within their expected distributions indicate good fit of the model for the particular characteristics of the data measured by those statistics. The blue dashed lines show values computed for the eight-pattern-s (37 crypts) dataset, whereas black solid lines correspond to computations for the 24-pattern dataset (left and middle: 20 crypts; right: 13 crypts).
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pcbi-0030028-g003: Assessment of Model Fitness(Left) Model with independent sites. (Middle) Model with context-dependent methylation rate. (Right) Model with context-dependent methylation rate without data from patient X.Five within-crypt statistics are examined (in rows). For each of these statistics, the observed intercrypt average and standard deviation are plotted (vertical lines) along with their expected distribution given the posterior of the parameters. Statistics that fall within their expected distributions indicate good fit of the model for the particular characteristics of the data measured by those statistics. The blue dashed lines show values computed for the eight-pattern-s (37 crypts) dataset, whereas black solid lines correspond to computations for the 24-pattern dataset (left and middle: 20 crypts; right: 13 crypts).

Mentions: Expected distributions and empirical values of the five statistics are plotted in Figure 3. The fit of the model with context-dependent methylation rate is much better than the fit of the model with independent sites. This can be seen for instance in the average and standard deviation of the number of distinct patterns per crypt; in the standard deviation of the average distance between patterns of the same crypt; or in the average number of unmethylated patterns.


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)

Assessment of Model Fitness(Left) Model with independent sites. (Middle) Model with context-dependent methylation rate. (Right) Model with context-dependent methylation rate without data from patient X.Five within-crypt statistics are examined (in rows). For each of these statistics, the observed intercrypt average and standard deviation are plotted (vertical lines) along with their expected distribution given the posterior of the parameters. Statistics that fall within their expected distributions indicate good fit of the model for the particular characteristics of the data measured by those statistics. The blue dashed lines show values computed for the eight-pattern-s (37 crypts) dataset, whereas black solid lines correspond to computations for the 24-pattern dataset (left and middle: 20 crypts; right: 13 crypts).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0030028-g003: Assessment of Model Fitness(Left) Model with independent sites. (Middle) Model with context-dependent methylation rate. (Right) Model with context-dependent methylation rate without data from patient X.Five within-crypt statistics are examined (in rows). For each of these statistics, the observed intercrypt average and standard deviation are plotted (vertical lines) along with their expected distribution given the posterior of the parameters. Statistics that fall within their expected distributions indicate good fit of the model for the particular characteristics of the data measured by those statistics. The blue dashed lines show values computed for the eight-pattern-s (37 crypts) dataset, whereas black solid lines correspond to computations for the 24-pattern dataset (left and middle: 20 crypts; right: 13 crypts).
Mentions: Expected distributions and empirical values of the five statistics are plotted in Figure 3. The fit of the model with context-dependent methylation rate is much better than the fit of the model with independent sites. This can be seen for instance in the average and standard deviation of the number of distinct patterns per crypt; in the standard deviation of the average distance between patterns of the same crypt; or in the average number of unmethylated patterns.

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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