Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification

Abstract

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification.

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

“…The models that we use are easily extendible to other types of epigenetic regulation, as illustrated by earlier studies that have modelled epigenetic modification of histones with similar mathematical formulations. [13][14][15] Similarly, the recently discovered demethylation mechanisms based on base pair excision repair are not explicitely included in our model. However, we do account for aspecific degradation of methylation that can be due to DNA repair mechanisms.…”

“…Many areas of research make use of the concept of switching between alternative attractors, e.g. in ecology, 68 developmental biology, 69 gene regulation studies on the Lac operon, 8 systems biology, 70 epigenetic regulation 13 and haematology. [10][11][12] All models used in these fields share the key feature of cooperative (i.e., nonlinear) positive feedback that fosters the formation of multiple attractors.…”

“…[9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models. [13][14][15] At the molecular level these mathematical models describe quite different genetic and epigenetic systems. Mathematically they share important features, such as the presence of alternative phenotypes resulting from the nonlinearities implied by cooperative self-activation (that is, nonlinear positive feedback, see Box 1).…”

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

“…The more stringent version concerns stable heritable bistability in which epigenetic information can be transmitted for, in principle, an infinite number of generations, depending on the strength of the bistability of the underlying system. As shown by Dodd et al (2007), this requires cooperative, positive feedback recruitment reactions as well as non-local interactions. A recent review of formal modeling approaches to the dynamics and propagation of histone modifications has been provided by Rohlf et al (2012).…”

“…In contrast, the maintenance of local patterns of histone modifications over a limited number of somatic cell divisions can potentially violate the conditions for long-term stability and tolerate slow accumulation of errors. In this setting it makes sense, therefore, to dispense with the stringent requirements outlined by Dodd et al (2007). Indeed, it appears that this less stringent version is the relevant mechanism in multi-cellular organisms, as cells only replicate a limited number of times (the Hayflick limit).…”