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Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration.

Developmental cell (2021-08-01)
Litao Tao, Haoze V Yu, Juan Llamas, Talon Trecek, Xizi Wang, Zlatka Stojanova, Andrew K Groves, Neil Segil
ANOTACE

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.

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γ-Secretase Inhibitor IX, Gamma-Secretase Inhibitor IX - CAS 208255-80-5, is a cell-permeable inhibitor of γ-secretase (Aβtotal IC₅₀ = 115 nM, Aβ42 IC₅₀ = 200 nM).
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(Z)-4-Hydroxytamoxifen, ≥98% Z isomer
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Trichostatin A, Ready Made Solution, 5 mM in DMSO, from Streptomyces sp.
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GSK-LSD1, ≥98% (HPLC)