Planarian Flatworms As a New Model System for Understanding the Epigenetic Regulation of Stem Cell Pluripotency and Differentiation

Planarian flatworms possess pluripotent stem cells (neoblasts) that are able to differentiate into all cell types that constitute the adult body plan. Consequently, planarians possess remarkable regenerative capabilities. Transcriptomic studies have revealed that gene expression is coordinated to maintain neoblast pluripotency, and ensure correct lineage specification during differentiation. But as yet they have not revealed how this regulation of expression is controlled. In this review, we propose that planarians represent a unique and effective system to study the epigenetic regulation of these processes in an in vivo context. We consolidate evidence suggesting that although DNA methylation is likely present in some flatworm lineages, it does not regulate neoblast function in Schmidtea mediterranea. A number of phenotypic studies have documented the role of histone modification and chromatin remodelling complexes in regulating distinct neoblast processes, and we focus on four important examples of planarian epigenetic regulators: Nucleosome Remodeling Deacetylase (NuRD) complex, Polycomb Repressive Complex (PRC), the SET1/MLL methyltransferases, and the nuclear PIWI/piRNA complex. Given the recent advent of ChIP-seq in planarians, we propose future avenues of research that will identify the genomic targets of these complexes allowing for a clearer picture of how neoblast processes are coordinated at the epigenetic level. These insights into neoblast biology may be directly relevant to mammalian stem cells and disease. The unique biology of planarians will also allow us to investigate how extracellular signals feed into epigenetic regulatory networks to govern concerted neoblast responses during regenerative polarity, tissue patterning, and remodelling.