H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium [regen_cutandtag_mouse]

Cell plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is highly stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration. While precise gene expression is needed to control these processes, the regulatory mechanisms that restrict or promote cell plasticity are poorly understood. Here, we use the mouse small intestine as a model system to study cell plasticity. We find that H3K36 methylation reinforces expression of cell type-associated genes to maintain specialized cell identity in intestinal epithelial cells. Depleting H3K36 methylation leads to defects in lineage commitment and activates a plastic, regenerative gene expression signature. Correspondingly, we observe rapid and reversible remodeling of H3K36 methylation following injury-induced regeneration. Together, these data suggest a fundamental role for H3K36 methylation in regulating cell plasticity and regeneration.