Conservation of epigenetic regulation by the MLL3/4 tumour suppressor in planarian pluripotent stem cells

Currently, little is known about the evolution of epigenetic regulation in animal stem cells. Using the planarian stem cell system to investigate the role of the COMPASS family of MLL3/4 histone methyltransferases, we demonstrate that their role as tumour suppressors in stem cells is conserved over a large evolutionary distance in animals. This also suggested the potential conservation of a genome wide epigenetic regulation program in animal stem cells, so we assessed the regulatory effects of Mll3/4 loss of function by performing RNA-seq and ChIP-seq on the G2/M planarian stem cell population, part of which contributes to the formation of outgrowths. We find many oncogenes and tumour suppressors among the affected genes that are therefore likely candidates for mediating MLL3/4 tumour suppression function in mammals, where little is known about in vivo regulatory targets. Our work demonstrates conservation of an important epigenetic regulatory program in animals and highlights the utility of the planarian model system for studying epigenetic regulation.