Compromised　learning　and　memory　is　a　common　feature　of　multiple　neurodegenerative　disorders.　A　paradigm　spatial　memory　impairment　could　be　caused　by　developmental　lead　(Pb)　exposure.　Growing　evidence　implicates　epigenetic　modifications　in　the　Pb-mediated　memory　deficits;　however,　how　histone　modifications　exemplified　by　H3K27me3　(H3　Lys27　trimethylation)　contribute　to　this　pathogenesis　remains　poorly　understood.　Here　we　found　that　Pb　exposure　diminished　H3K27me3　levels　in　vivo　by　suppressing　EZH2　(enhancer　of　zeste　homolog　2)　expression　at　an　early　stage.　EZH2　overexpression　in　Pb-treated　rats　rescued　the　H3K27me3　abundance　and　partially　restored　the　normal　spatial　memory,　as　manifested　by　the　rat　performance　in　a　Morris　water　maze　test,　and　structural　analysis　of　hippocampal　spine　densities.　Furthermore,　miR-137　and　EZH2　constitute　mutually　inhibitory　loop　to　regulate　the　H3K27me3　level,　and　this　feedback　regulation　could　be　specifically　activated　by　Pb　treatment.　Considering　genes　targeted　by　H3K27me3,　ChIP-chip　(chromatin　immunoprecipitation　on　chip)　studies　revealed　that　Pb　could　remodel　the　genome-wide　distribution　of　H3K27me3,　represented　by　pathways　like　transcriptional　regulation,　developmental　regulation,　cell　motion,　and　apoptosis,　as　well　as　a　novel　Wnt9b　locus.　As　a　Wnt　isoform　associated　with　canonical　and　noncanonical　signaling,　Wnt9b　was　regulated　by　the　opposite　modifications　of　H3K4me3　(H3　Lys4　trimethylation)　and　H3K27me3　in　Pb-exposed　neurons.　Rescue　trials　further　validated　the　contribution　of　Wnt9b　to　Pb-induced　neuronal　impairments,　wherein　canonical　or　noncanonical　Wnt　signaling　potentially　exhibited　destructive　or　protective　roles,　respectively.　In　summary,　the　study　reveals　an　epigenetic-based　molecular　change　underlying　Pb-triggered　spatial　memory　deficits,　and　provides　new　potential　avenues　for　our　understanding　of　neurodegenerative　diseases　with　environmental　etiology.