The epigenetic basis of cellular plasticity

Abstract

Cellular plasticity is now recognized as a fundamental feature of tissue biology. The steady-state differentiation of stem and progenitor cells into mature cells is, in itself, the index form of cellular plasticity in adult organisms. Following injury, when it is critical to quickly regenerate and restore tissue integrity and function, other types of cellular plasticity may be crucial for organismal survival. In these contexts, alterations in the epigenetic landscape of tissues are likely to occur in order to allow normally restricted cell fate transitions. Epigenetic mechanisms, particularly DNA methylation and histone modifications, have been shown to play an important role in regulating such plasticity. Relevant mechanisms have been well studied in the context of the direct reprograming of somatic cells into induced pluripotent stem cells. Indeed, epigenetic regulation of cell fate is part and parcel of normal embryonic development and is a central regulator of cellular diversity. This is normally thought to involve the establishment of divergent chromatin patterns that culminate in cells with distinct and what were previously thought to be irreversible fates. This brief review aims to put some of these new observations in the larger context of regeneration after injury.

Figure 1. Intestinal progenitors maintain an accessible chromatin state that underlies cell plasticity

Although chromatin states become restricted in the course of the differentiation of intestinal stem cells into mature secretory and enterocyte cells, secretory progenitor cells maintain an open chromatin configuration at enterocyte loci that allows the conversion of secretory into enterocyte progenitors (normally regulated by lateral inhibition). Specifically, upon the loss of a secretory transcription factor, the secretory progenitor cell transdifferentiates into an enterocyte progenitor cell. Blue: secretory-associated factors; yellow: enterocyte-associated factors.

Figure 2. Epicenters located within super enhancers govern normal epithelial cell fate and wound repair requires the dual activation of epidermal and hair follicle gene expression through a wound-specific epicenter

(A) The epidermis and hair follicle represent two distinct cell fates that are maintained by separate stem cells. The epidermal stem cells express Klf5 and the hair follicle stem cells express Sox9. In each case, their expression is regulated by a specific epicenter within a larger super enhancer. (B) In the case of wounding, stress-induced regulatory elements are activated to transiently allow cell plasticity. A new wound epicenter results in the co-expression of Klf5 and Sox9. This transient co-expression of epidermal and hair follicle genes is required for wound repair. (C) In tumors, the expression of stress-induced and epidermal and hair follicle lineage-specific transcription factors are sustained, resulting in the expression of oncogenes. This induction is engendered through the formation of a new tumor epicenter that occurs alongside a wound epicenter. Blue: epidermis; yellow: hair follicle; magenta: wound; black: tumor.