Advanced paternal age exacerbates neuroinflammation in offspring via m6A modification-mediated intergenerational inheritance.

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2024-10-04 DOI:10.1186/s12974-024-03248-8

Yiting Mao, Yicong Meng, Kexin Zou, Ningxin Qin, Yinyu Wang, Jing Yan, PinJia Chen, Yi Cheng, Weihui Shi, Chengliang Zhou, Huixi Chen, Jianzhong Sheng, Xinmei Liu, Jiexue Pan, Hefeng Huang

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引用次数: 0

Abstract

Background: The trend of postponing childbearing age is prevalent worldwide. Advanced paternal age (APA) is associated with adverse pregnancy outcomes and offspring health. However, the underlying mechanism by which paternal aging affects the risk of offspring neuropsychiatric disorders is unclear. Our study aims to explore the behavioral phenotypes and the pathologic epigenetic alterations of APA offspring inherited from aging sperm.

Methods: Behavioral tests, ELISA assay, immunofluorescence and western blotting were performed on offspring mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) were used to investigate the modified N6-methyladenosine (m6A) profiles of paternal sperm and offspring hippocampus. Intervention of gene expression by lentivirus and adeno-associated virus in both vivo and vitro examined the potential therapeutic targets of intergenerational inherited neuroinflammation.

Results: In our study, APA offspring exhibit cognitive impairment and autism-like behavior. An increase in neuroinflammation in APA offspring is associated with microglial overactivation, which manifests as abnormal morphology and augmented engulfment. MeRIP-seq of F0 sperm and F1 hippocampus reveal that Nr4a2 is hypermethylated with decreased expression in APA offspring involving in synaptic plasticity and microglial function. In addition, Ythdc1, an m6A reader protein, is markedly elevated in aging sperm and remains elevated in adult hippocampus of APA group. Enhanced Ythdc1 recognizes and suppresses the hypermethylated Nr4a2, thereby contributing to the abnormal phenotype in offspring. The overexpression of Ythdc1 triggers microglial activation in vitro and its suppression in the hippocampus of APA progeny alleviates behavioral aberrations and attenuates neuroinflammation.

Conclusion: Our study provides additional evidence of the abnormal behavioral phenotypes of APA offspring and reveals potential epigenetic inheritance signatures and targeted genes for future research.

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父亲高龄会通过 m6A 修饰介导的代际遗传加剧后代的神经炎症。

背景：推迟生育年龄的趋势在全世界都很普遍。高龄产妇（APA）与不良妊娠结局和后代健康有关。然而，父亲高龄化影响后代神经精神疾病风险的潜在机制尚不清楚。我们的研究旨在探索高龄精子遗传给 APA 后代的行为表型和病理表观遗传学改变：方法：对后代小鼠进行行为测试、ELISA检测、免疫荧光和Western印迹。甲基化RNA免疫沉淀测序（MeRIP-seq）和RNA免疫沉淀测序（RIP-seq）用于研究父代精子和子代海马的N6-甲基腺苷（m6A）修饰谱。通过慢病毒和腺相关病毒对体内和体外基因表达的干预，研究了代际遗传性神经炎症的潜在治疗靶点：在我们的研究中，APA 的后代表现出认知障碍和类似自闭症的行为。APA后代神经炎症的增加与小胶质细胞过度激活有关，表现为形态异常和吞噬作用增强。对F0精子和F1海马的MeRIP-seq分析显示，在APA后代中，Nr4a2的甲基化程度过高，表达量减少，而Nr4a2参与突触可塑性和小胶质细胞功能。此外，m6A 读取蛋白 Ythdc1 在衰老精子中明显升高，在 APA 组的成年海马中仍然升高。增强的 Ythdc1 能识别并抑制高甲基化的 Nr4a2，从而导致后代的异常表型。Ythdc1在体外过表达会引发小胶质细胞活化，而在APA后代的海马中抑制Ythdc1会缓解行为异常并减轻神经炎症：我们的研究为 APA 后代的异常行为表型提供了更多证据，并为未来研究揭示了潜在的表观遗传特征和靶向基因。

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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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.