Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Xiaozhen Gu,Wei-Zhen Xue,Hui-Li Wang,Zi Ye,Yulan Wu,Guiran Xiao,Yi Xu

doi:10.1038/s41419-019-1912-7

Xiaozhen Gu, Wei-Zhen Xue + Show 5 more

Open Access

https://doi.org/10.1038/s41419-019-1912-7

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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.

Highlights

Learning and memory deficits are the important symptoms contributing to the development of an array of neurodegenerative diseases, such as Alzheimer’s disease[1] and non-motor aspects of Parkinson’s disease[2]
Pb reduces H3K27me[3] levels via suppressing enhancer of zeste homolog 2 (EZH2) expression at early developmental stage Since H3K27me[3] is a stable epigenetic marker[21], we first investigated if its level could be altered by Pb exposure
Primary hippocampal neurons were exposed to 5 μM Pb from days in vitro 3 (DIV3) and collected at DIV14 for protein extraction

Summary

Introduction

Learning and memory deficits are the important symptoms contributing to the development of an array of neurodegenerative diseases, such as Alzheimer’s disease[1] and non-motor aspects of Parkinson’s disease[2]. The hippocampal region stores information about allocentric spaces[3,4]; damage to hippocampal development frequently leads to memory dysfunction. Lead (Pb) prevails as a causative agent of hippocampal neuronal death and cognitive dysfunction, leading to the typical neurotoxicity characterized by region-specific, long-lasting, altered spine morphology, among others[5,6,7]. Given that Pb exposure results in typical spatial memory deficit, efforts were made to investigate the molecular pathways involved in this specific pathogenesis[8,9,10]. Epigenetic modifications regulate gene expression by altering accessibility of genomic loci to the transcription machinery[11,12].

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