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Abstract
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.
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1 School of Food and Bioengineering, Hefei University of Technology, Hefei, Anhui, People’s Republic of China
2 College of Life Science and Bio-engineering, Beijing University of Technology, Beijing, People’s Republic of China