How cells transition from one state to another in vivo is a key question in biological sciences, with particular importance for the study of organismal development, carcinogenesis, and pluripotent reprogramming. In the early days of developmental biology, Conrad Waddington used the term ‘Epigenetics’ to refer to the process by which a cell transitions from one state to another during development, and how cells might be influenced by interactions between genes and their environment. Since this time, ‘Epigenetics’ as been redefined many times over, and now the definition includes many molecular mechanisms for regulating gene activation or silencing (among others). Nonetheless, we as a field still do not fully understand how epigenetic mechanisms direct cell fate decisions. My work is focused precisely on this issue, but also encompasses how epigenetic marks might be inherited from one generation to the next.
Cell State Transition –
Leaders in the epigenetics field, including Dr. Brad Bernstein and Dr. Andy Feinberg, have developed elegant models to explain the role of epigenetic marks in cell state conversion, including during carcinogenesis. In Dr. Bernstein’s model, in order for a given cell to transition from one cell type to another, it must overcome an “energy wall.” In this model, epigenetic marks have the capacity to either raise or lower the “energy wall” and make it more difficult or easier for a given cell to transition between states. He refers to this low “energy wall” state as the “Plasticity” state. In this state, the “energy wall” is consistently low, and a cell might move more easily between states, and thus, contribute to carcinogenesis.
Dr. Feinberg’s model is quite similar to Dr. Bernstein’s, except it incorporates Waddington’s Epigenetic Landscape. Here, during normal development a given stem cell rolls downhill through the Landscape, and as it rolls it becomes confined within a particular cavernous valley (or lineage), where it is restricted, and eventually the cell comes to rest in a terminally differentiated state. In Dr. Feinberg’s model, a cell also has the potential to enter an alternative “Neoplasia” trajectory, where the valleys are much more shallow than the valleys of “Normal Development”, and therefore, the cell has a greater capacity to transition back and fourth from one state to another. In this model, the depths of the valleys are similar to the “energy walls” from Dr. Bernstein’s model.
Plasticity during normal development –
I propose that cells enter a transition state, similar to Dr. Bernstein’s “Plasticity” state, during normal development, as they transition from one cell type to another. In the context of Waddington’s Landscape, this state might occur at the branch point between two valleys, immediately before a cell falls into one of two valleys and becomes committed to a particular lineage. I also hypothesize that the Placeholder nucleosome, which I previously characterized to enable DNA demethylation during germline-to-embryo transition (Recent Results), might function during developmental lineage transition points to lower “energy walls” and enable cell state transitions.
Placeholder enables the “Plasticity State”
In my previous work, I identified a set of unique characteristics that associate with Placeholder localization and Placeholder stability throughout the genome. These less stable, or “susceptible” loci happen to overlap with enhancer regions, and associate with genes important for embryonic development and lineage commitment. I propose that during differentiation, Placeholder is reorganized throughout the genome (specifically at these susceptible loci), to maintain new sites of DNA demethylation and to enable tissue specific enhancer activation. Thus, Placeholder reorganization at enhancers might lower the “energy wall”, and facilitate a transient “Plasticity” state for a given cell during development. I also argue that Placeholder nucleosomes might serve a similar function during carcinogenesis to allow a terminally differentiated cell to transition to a new cell state. Here, mislocalization of Placeholder would lower the “energy wall”, lead to a continuous “Plasticity”, and potentially contribute to tumorigenesis.