Early-Life Adversity–Induced Epigenetic Reprogramming of Prefrontal Cortex in Rats Subjected to Maternal Separation

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science Pub Date : 2025-03-20 DOI:10.1016/j.bpsgos.2025.100487

Aleena Francis , Lauren Allen McKibben , Yogesh Dwivedi

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引用次数: 0

Abstract

Background

Early-life adversity (ELA) can lead to long-lasting behavioral and neurobiological changes through epigenetic mechanisms. In this study, we comprehensively mapped genome-wide DNA methylation in the prefrontal cortex of rats following maternal separation (MS).

Methods

Rat pups were separated from their mother for 180 minutes/day from postnatal days (PNDs) 1 to 14 and tested for depressive- and anxiety-like behavior during adulthood (PNDs 80–89). Genome-wide DNA methylation, corresponding functional analyses, and transcription factor binding sites (TFBSs) were performed using reduced-representation bisulfite sequencing, focusing on differentially methylated cytosines (DMCs), differentially methylated regions (DMRs), and non-CpG sites.

Results

Both male and female MS rats showed a significant decrease in sucrose preference. Principal component and multidimensional scaling analyses did not show differences in the methylation data between male and female rats, prompting us to combine them in subsequent analyses. A total of 33,905 DMCs and 151 DMRs were identified in the MS group. The functional analysis of the dysregulated genes by DMCs and DMRs in the promoter or gene body revealed gene enrichment involved in neurodevelopment, synaptic plasticity, and stress response. Key genes with altered methylation included Dnmt3a/b, Notch1, Mapk14, and calcium channel subunits. Gene network analysis revealed interactions among ribosomal, MAPK (mitogen-activated protein kinase), and glutamatergic pathway genes. An enrichment of Elk1 TFBSs was particularly noted within the DMR. Additionally, differential non-CpG methylation, specifically at CHH (H = C/T/A) sites, dysregulated the Wnt pathway genes.

Conclusions

Our findings expand our understanding of the molecular mechanisms that underlie the long-term effects of ELA and identify potential biomarkers for stress-related psychiatric disorders.

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母亲分离大鼠早期逆境诱导的前额叶皮层表观遗传重编程

童年逆境（ELA）可以通过表观遗传机制导致长期的行为和神经生物学变化。在这项研究中，我们全面绘制了母系分离（MS）后大鼠前额皮质全基因组DNA甲基化图谱。方法从出生后第1 ~ 14天（PNDs）开始，将幼鼠与母鼠分离180分钟/天，并在成年期（PNDs 80 ~ 89）检测抑郁和焦虑样行为。全基因组DNA甲基化、相应的功能分析和转录因子结合位点（TFBSs）使用减少代表性亚硫酸盐测序进行，重点是差异甲基化胞嘧啶（DMCs）、差异甲基化区域（DMRs）和非cpg位点。结果雄性和雌性MS大鼠对蔗糖的偏好均显著降低。主成分分析和多维尺度分析没有显示雄性和雌性大鼠之间甲基化数据的差异，这促使我们在随后的分析中结合它们。MS组共鉴定出33,905个dmc和151个DMRs。DMCs和DMRs对启动子或基因体中失调基因的功能分析揭示了参与神经发育、突触可塑性和应激反应的基因富集。甲基化改变的关键基因包括Dnmt3a/b、Notch1、Mapk14和钙通道亚基。基因网络分析揭示了核糖体、MAPK（丝裂原活化蛋白激酶）和谷氨酸能途径基因之间的相互作用。在DMR中特别注意到Elk1 TFBSs的富集。此外，差异的非cpg甲基化，特别是在CHH （H = C/T/A）位点，失调了Wnt通路基因。结论我们的发现扩大了我们对ELA长期影响的分子机制的理解，并确定了应激相关精神疾病的潜在生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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