Coordinated changes in multiple gene networks are emerging to be a key determinant of axon regeneration.Epigenetic regulation of chromatin structure is emerging to be a key cellular mechanism to coordinate gene expression,making it a novel mechanism for regulation of neural regeneration.Here we found thathistone methyltransferase EZH2,which methylatesH3 histone at lysine 27(H3K27),was drastically up regulated in mouse sensory neurons after peripheral axotomy,whereas H3K27 demethylases JMJD3/UTX were markedly down regulated,leading to markedly increased trimethylation level of H3K27.These results suggested that H3K27 methylation might be a novel regulatory mechanism for axon regeneration.Indeed,conditionallyknocking out EZH2 significantly reduced the level of H3K27 trimethylation and impaired sensory axon regeneration in vivo.Conversely,down regulation of JMJD3 significantly promoted sensory axon regeneration in vivo.Furthermore,we identified transcription factor KLF4 as a direct target gene repressed by H3K27 trimethylation.We also performed ChIP-seq using H3K27me3 antibody in regenerating sensory neurons and bioinformatics analysis identified a network of genes that might function to regulate neural regeneration.Lastly,we showed that knocking out UTX in mouse retinal ganglion cells drastically promoted long distance optic nerve regeneration.Together,our study 1)elucidated a novel mechanism that regulates mammalian axon regeneration via histone methylation,2)identified a mechanistically novel approach for promoting neural regeneration in the mammalian central nervous system,and 3)established axon injury as a useful and physiological relevant model for studying epigenetic regulation of gene expression beyond the field of neural regeneration.