Drawing on disorder: How viruses use histone mimicry to their advantage

Tarakhovsky, Alexander; Prinjha, Rab K.

To generate the viral infection state, viruses must overcome the robustness of the infected cell phenotype. In development, robustness is described as canalization, whereby developing cells are directed toward a specific outcome from uncertain starting conditions and despite various cellular and environmental perturbations (Waddington, 1942) . In Waddington's "epigenetic landscape," environmental influences lead to the establishment of "valleys" that guide the direction of genetic processes and define a generation of cell types with a discrete nature (Waddington, 1942) . Accordingly, distinct cell phenotypes are represented by the placement of a cell state within a particular valley ( Fig. 1 A) . The Waddington landscape is not just a metaphor but rather an accurate reflection of the state of gene regulatory networks that operate within cells (Huang et al., 2005) . The gene expression levels in the cells can be viewed within the high-dimensional state space, where each point in the state space represents one gene expression pattern within the gene regulatory network ( Fig. 1 B) . The convergence of individual dimensions, i.e., gene expression trajectories, from the high energy, unstable state to the low energy, stable state generates the so-called attractor state, toward which specific cells are pulled over time (Macarthur et al., 2009; Fig. 1 C) . The stable attractor state occupies the basin of the state space and is surrounded by unstable states. Such topography provides an explanation for the self-stabilizing nature of gene networks where the hills that separate attractors represent unstable network states. It has been proposed that attractor states define the stable phenotypes of specific cell types (Sooranna and Saggerson, 1979; Huang et al., 2009 ). The self-organizing and self-stabilizing property of the cell state, which defines gene expression profiles, is a natural feature conferred by attractors. The attractor state can be reached via an almost infinite number of paths, all of which lead to cell type-specific gene expression patterns that are highly resistant to noise and can reestablish themselves after small perturbations . However, in the presence of sufficiently high levels of fluctuations or in response to a deterministic signal, cells can switch between attractors and generate new and potentially heritable phenotypes (Kalmar et al., 2009; Muñoz-Descalzo et al., 2012; Li et al., 2016) .