Regulated noise in the epigenetic landscape of development and disease

Abstract

In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity.

Figure 1. VMRs in cancer are LOCKs in developmental reprogramming

Large variably methylated regions (VMRs) in cancer (top panel) were identified by whole genome bisulfite sequencing. These VMRs are hypomethylated in cancer and largely correspond to nuclear lamina-associated large organized chromatin lysine (K)-modifications (LOCKs), which can be visualized by electron microscopy (lower panel) and native chromatin immunoprecipitation (right panels schematic and data). Epithelial-mesenchymal transition (EMT) is mediated by loss of LOCKs. Inducible increased variance is a normal part of cellular reprogramming and is aberrantly activated, seemingly universally in cancer. Images reprinted by permission from Hansen et al. (2011) and McDonald et al. (2011).

Figure 2. Regulated noise in a dynamic epigenetic landscape

On the left is a representation of the classical Waddington representation of canalization, in which the ball rolling down the hill is directed into one of three valleys and a consistent endpoint, despite perturbation that might occur on the way. Waddington suggested a deterministic model with genes (small rectangles below) pulling on the landscape from below to direct these endpoints. Changes in the landscape would arise by mutations in the genes. On the right, we suggest that noise is itself regulated during development and in response to external cues, which affects the contour of the epigenetic landscape itself. During differentiation, as the ball rolls down the hill, nuclear structure changes in a metastable manner through, for example structures such as LOCKs and methylated blocks, changing the steepness of the valleys. At the same time, new chromosomal interactions could increase localized variance in ways that were not possible at the ground state; in this case changing the landscape to open an alternative pathway to diversity (new bifurcation shown below the ball). The other shapes represent chromatin modifications (red circle), DNA methylation (blue), lamin proteins (green), and chromosome interactome mediators (red pentagon).