Orchestrating differentiation by signalling to the polycomb repressive complex
FGF/Erk1/2 signalling maintains an undifferentiated progenitor cell state in many developing tissues. In the elongating body axis, such signalling is active in the tailbud and maintains, along with Wnt, axial progenitors that give rise to neural and mesodermal cells. Previous work has shown that loss of FGF signalling promotes onset of neural differentiation as epiblast cells leave the tailbud, and specifically elicits chromatin decompaction around neural differentiation gene loci. In this talk I will present recent findings which show that inhibition of Erk activity mediates rapid decompaction around the neural differentiation gene Pax6 in mouse embryos and in human spinal cord precursors in vitro and that this involves dissociation of the polycomb-repressive-complex. Using ATAC-Seq we further demonstrate that Erk dephosphorylation increases chromatin accessibility across hundreds of neural differentiation genes. Our findings suggest that decline in FGF/ERK signalling and hence polycomb occupancy synchronizes the onset of neural gene expression. Moreover, the polycomb-repressive-complex represses but also poises genes for transcription and these data therefore suggest that ERK promotion of this complex is a rite of passage for subsequent differentiation.
Kate Storey is head of the Division of Cell & Developmental Biology and Chair of Neural Development, in the School of Life Sciences, at the University of Dundee. Research in the Storey group involves investigation of the cellular and molecular mechanisms regulating neural differentiation in chick and mouse embryos and embryonic stem (ES) cells. Storey has pioneered innovative live imaging approaches for monitoring behaviour and signalling of individual cells within developing tissues. These approaches have led to discovery of a new form of cell sub-division, named apical abscission, as well as providing insights into cell signalling dynamics that underpin asymmetric cell division. Her early work uncovered a fundamental signalling switch regulating the onset of neural differentiation. More recent findings link a component of this, FGF/ERK signalling, to molecular machinery regulating chromatin accessibility at neural differentiation gene loci. Storey’s discovery of this signalling switch has further informed in vitro differentiation protocols for mouse and human ES cells and has facilitated new work identifying mechanisms that regulate human neurogenesis