The Tick-Tock of the Molecular Clock: Random methylation state changes inform homeostasis in the intestinal crypt

The small intestinal and colon crypts are hierarchical, dynamic systems. Small numbers of stem cells give rise to daughter cells which proliferate within the transient amplifying zone, giving rise to a differentiated cell population. Stem cell numbers are constant, but survival is stochastic because divisions may result in renewal, expansion, or extinction. This hierarchy is largely maintained even in the face of disease and early dysplasias, where the microenvironment strives to re-establish homeostasis. Surprisingly, little is known about the stem cell numbers within these crypts. We use a distribution of CpG sites taken from four individual crypts across 60 patients to integrate with a statistical fitting approach and an agent based mechanistic model of the homeostatic crypt. Using this integrative approach we are better able to understand the dynamics of the stem cell pool. Most notably, using this method we can determine the number of stem cells and estimation of the error rates associated with DNA methyltransferase during cell division. The model splits the crypt into two compartments, the base and body of the crypt, and incorporates base pair resolution genomes and CpG sites. We calibrate our exclamatory bowel model with normal human small intestinal and colon crypt data using Approximate Bayesian Computation. This approach provides numerous insights into the dynamics of aging and underlying diseases within human crypts. The model can also be used to investigate why small intestinal crypts rarely develop cancers while colon cancer is frequently seen.