Epigenetic control of planarian stem cell potency limits stem activity and accurately defines differentiation programs

Planarian flatworms are gaining popularity in regenerative medicine research due to the fact that they have unparalleled regeneration capacity. Their tissue recovery abilities are dependent on a pool of adult stem cells (neoblasts). Studies in the recent years have shown that epigenetic mechanisms have an important role in neoblasts’ self-renewal and differentiation properties. This thesis focuses on the study of trithorax-related genes and their function in neoblast regulation. Despite the fact that mammalian trithorax-related genes Mll3 and Mll4 are among the most frequently mutated genes in cancer, trithorax-related genes are the least well-studies members of the trithorax gene group (TrxG) of histone modifiers. The current study traced the evolutionary history of trithorax-related genes and concluded that they have undergone a number of independent gene fission events across phyla. In planarians, there are three partial orthologue of the mammalian Mll3 and Mll4 genes – Smed-LPT (corresponding to the N-terminus of Mll3/4), Smed-trr-1 and Smed-trr-2 (both corresponding to the C-terminus of Mll3/4). The three planarian trithorax-related genes are expressed in stem cells and control neoblast differentiation down certain lineages (brain, gut, eyes, pharynx, epidermis). Down-regulation of Smed-LPT results in hyperproliferation of stem cells, leading to tumour-like outgrowth formation. It was shown that trithorax-related genes’ function in stem cell regulation correlates with histone modification changes, specifically alterations in H3K4me1, H3K4me3 and H3K27me3. Future studies will focus on examining this correlation further via Next-Generation sequencing techniques