Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies

Abstract

For decades, Waddington's concept of the 'epigenetic landscape' has served as an educative hierarchical model to illustrate the progressive restriction of cell differentiation potential during normal development. While still being highly valuable in the context of normal development, the Waddington model falls short of accommodating recent breakthroughs in cell programming. The advent of induced pluripotent stem (iPS) cells and advances in direct cell fate conversion (also known as transdifferentiation) suggest that somatic and pluripotent cell fates can be interconverted without transiting through distinct hierarchies. We propose a non-hierarchical 'epigenetic disc' model to explain such cell fate transitions, which provides an alternative landscape for modelling cell programming and reprogramming.