Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration

Abstract Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. The roles of two histone 3 lysine 27 (H3K27) demethylases, Kdm6a/b, in controlling neuroprotection and axon regeneration are investigated here. Deleting either Kdm6a or Kdm6b leads to enhanced sensory axon regeneration in the peripheral nervous system (PNS), whereas in the central nervous system (CNS), only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhances optic nerve regeneration. Moreover, both Kdm6a and Kdm6b function to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten, and co‐deleting Kdm6a and Pten results in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA‐seq profiling reveals that Kdm6a deletion switches the RGC transcriptomics into a developmental‐like state and suppresses several known repressors of neural regeneration. Klf4 is identified as a direct downstream target of Kdm6a‐H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only reveal different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identify Kdm6a‐mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.