Limits...
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.

Show MeSH
Posterior Correlation between N and αThe posterior of N subject to the constraint α = 0, 0.01, 0.02, or 0.03 (dotted lines) are compared with the posterior of N without those constraints (solid line).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC1808490&req=5

pcbi-0030028-g007: Posterior Correlation between N and αThe posterior of N subject to the constraint α = 0, 0.01, 0.02, or 0.03 (dotted lines) are compared with the posterior of N without those constraints (solid line).

Mentions: Unconstrained posterior inference suggests that the high level of intracrypt polymorphism is due to the existence of many stem cells in each crypt (high N). An alternative explanation for this high level of polymorphism could be a significant amount of methylation/demethylation events taking place in differentiation lineages (high α). Although this hypothesis does not receive support from our analysis, a closer look at the posterior reveals a negative correlation between N and α shown in Figure 7. The posterior of N for values of α below 0.01 virtually excludes values of N below ten, but a number of stem cells below ten becomes likely when α increases. These observations allow a better interpretation of the posterior of α and N obtained in the unconstrained analysis: a number of stem cells between eight and ten is unlikely but may be compatible with the data if α > 0.01. In the context of a niche succession time of 20 years, this would indicate that the rate of methylation/demethylation is enhanced during cell differentiation.


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)

Posterior Correlation between N and αThe posterior of N subject to the constraint α = 0, 0.01, 0.02, or 0.03 (dotted lines) are compared with the posterior of N without those constraints (solid line).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0030028-g007: Posterior Correlation between N and αThe posterior of N subject to the constraint α = 0, 0.01, 0.02, or 0.03 (dotted lines) are compared with the posterior of N without those constraints (solid line).
Mentions: Unconstrained posterior inference suggests that the high level of intracrypt polymorphism is due to the existence of many stem cells in each crypt (high N). An alternative explanation for this high level of polymorphism could be a significant amount of methylation/demethylation events taking place in differentiation lineages (high α). Although this hypothesis does not receive support from our analysis, a closer look at the posterior reveals a negative correlation between N and α shown in Figure 7. The posterior of N for values of α below 0.01 virtually excludes values of N below ten, but a number of stem cells below ten becomes likely when α increases. These observations allow a better interpretation of the posterior of α and N obtained in the unconstrained analysis: a number of stem cells between eight and ten is unlikely but may be compatible with the data if α > 0.01. In the context of a niche succession time of 20 years, this would indicate that the rate of methylation/demethylation is enhanced during cell differentiation.

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