Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration

Adult mammalian tissues such as heart, brain, retina, and the sensory structures of the inner ear do not effectively regenerate, although a latent capacity for regeneration exists at embryonic and perinatal times. We explored the epigenetic basis for this latent regenerative potential in the mouse inner ear and its rapid loss during maturation. In perinatal supporting cells, whose fate is maintained by Notch-mediated lateral inhibition, the hair cell enhancer network is epigenetically primed (H3K4me1) but silenced (active H3K27 de-acetylation and trimethylation). Blocking Notch signaling during the perinatal period of plasticity rapidly eliminates epigenetic silencing and allows supporting cells to transdifferentiate into hair cells. Importantly, H3K4me1 priming of the hair cell enhancers in supporting cells is removed during the first post-natal week, coinciding with the loss of transdifferentiation potential. We hypothesize that enhancer decommissioning during cochlear maturation contributes to the failure of hair cell regeneration in the mature organ of Corti. [Display omitted] •Hair cell enhancers in P1 support cells are epigenetically “primed but silenced”•Hair cell enhancers are decommissioned by H3K4me1-loss in maturing support cells•Enhancer decommissioning blocks supporting cell transdifferentiation•Inhibiting H3K4me1 demethylation extends perinatal transdifferentiation potential Mammals are unable to regenerate cochlear sensory hair cells, while other vertebrates preserve robust inner ear regenerative capacity. We show that epigenetic decommissioning of hair-cell-specific enhancers (removal of H3K4me1) in supporting cells during perinatal maturation contributes to loss of regenerative capacity in the mammalian inner ear.