Dynamics, stability and inheritance of somatic DNA methylation imprints

Computational and Systems Biology Program, Massachusetts Institute of Technology, Room 68-371, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Journal of Theoretical Biology (Impact Factor: 2.12). 11/2006; 242(4):890-9. DOI: 10.1016/j.jtbi.2006.05.012
Source: PubMed


Recent research highlights the role of CpG methylation in genomic imprinting, histone and chromatin modification, transcriptional regulation, and 'gene silencing' in cancer development. An unresolved issue, however, is the role of stable inheritance of factors that manage epigenetic imprints in renewing or expanding cell populations in soma. Here we propose a mathematical model of CpG methylation that is consistent with the cooperative roles of de novo and maintenance methylation. This model describes (1) the evolution of methylation imprints toward stable, yet noisy equilibria, (2) bifurcations in methylation levels, thus the dual stability of both hypo- and hypermethylated genomic regions, and (3) sporadic transitions from hypo- to hypermethylated equilibria as a result of methylation noise in a finite system of CpG sites. Our model not only affords an explanation of the persistent coexistence of these two equilibria, but also of sporadic changes of site-specific methylation levels that may alter preset epigenetic imprints in a renewing cell population.

Download full-text


Available from: Matthew Lorincz,
  • Source
    • "Markov chains, in both discrete and continuous time, have found widespread use throughout biology (Renshaw, 1993; Sontag et al., 2006; Ross, 2010, 2011; Black and McKane, 2012; Hauert and Imhof, 2012). They are useful as they are amenable to analysis due to the Markovian property but still incorporate the aspect of randomness which is vitally important to accurate modeling of many biological processes (Renshaw, 1993; Black and McKane, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We develop a new methodology for the efficient computation of epidemic final size distributions. We exploit a particular representation of the stochastic epidemic process to derive a method which is both computationally efficient and numerically stable. The algorithms we present are also physically transparent and so allow us to extend this method from the basic SIR model to a model with a phase-type infectious period and another with waning immunity. The underlying theory is applicable to many Markovian models where we wish to efficiently calculate hitting probabilities.
    Journal of Theoretical Biology 07/2014; 367. DOI:10.1016/j.jtbi.2014.11.029 · 2.12 Impact Factor
  • Source
    • "To account for changes of the DNA methylation, we applied the basic model of DNA methylation introduced by Sontag et al. (2006) which describes the parallel action of maintenance and de novo DNA methyltransferases (Smith & Meissner, 2013). In this Markov-chain model, CpGs can change their methylation states during cell division only. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During aging, a decline in stem cell function is observed in many tissues. This decline is accompanied by complex changes of the chromatin structure among them changes in histone modifications and DNA methylation which both affect transcription of a tissue-specific subset of genes. A mechanistic understanding of these age-associated processes, their interrelations and environmental dependence is currently lacking. Here, we discuss related questions on the molecular, cellular, and population level. We combine an individual cell-based model of stem cell populations with a model of epigenetic regulation of transcription. The novel model enables to simulate age-related changes of trimethylation of lysine 4 at histone H3 and of DNA methylation. These changes entail expression changes of genes that induce age-related phenotypes (ARPs) of cells. We compare age-related changes of regulatory states in quiescent stem cells occupying a niche with those observed in proliferating cells. Moreover, we analyze the impact of the activity of the involved epigenetic modifiers on these changes. We find that epigenetic aging strongly affects stem cell heterogeneity and that homing at stem cell niches retards epigenetic aging. Our model provides a mechanistic explanation how increased stem cell proliferation can lead to progeroid phenotypes. Adapting our model to properties observed for aged hematopoietic stem cell (HSC) clones, we predict that the hematopoietic ARP activates young HSCs and thereby retards aging of the entire HSC population. In addition, our model suggests that the experimentally observed high interindividual variance in HSC numbers originates in a variance of histone methyltransferase activity.
    Aging cell 01/2014; 13(2):320-328. DOI:10.1111/acel.12177 · 6.34 Impact Factor
  • Source
    • "A single or a few methylated CpGs within an overall unmethylated promoter region represent either technical (bisulfite conversion) errors or stochastic biological errors without functional consequences. Because individual CpGs cannot stably maintain methylation states that differ from those of the neighboring CpGs, usually the entire promoter is either methylated or not (7,36). Epigenetic silencing, i.e. of the somatostatin gene in gastric cancers, is characterized by an inverse correlation between the promoter methylation level and mRNA expression (37). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4%) patients with constitutive BRCA1 and three (0.5%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.
    Human Molecular Genetics 07/2012; 21(21):4669-79. DOI:10.1093/hmg/dds308 · 6.39 Impact Factor
Show more