Germ‐cell‐specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders
Germ‐cell‐specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders
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DOI：
10.1002/aur.2939
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发表时间：
2023-05
期刊：
影响因子：
4.7
通讯作者：
Sawako Furukawa;J. Nomura;Hiroaki Hanafusa;Hiroko Maegawa;Toru Takumi
中科院分区：
文献类型：
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作者：
Sawako Furukawa;J. Nomura;Hiroaki Hanafusa;Hiroko Maegawa;Toru Takumi
越来越多的流行病学研究表明，父亲受孕年龄越大，其子女患自闭症谱系障碍（ASD）等神经发育疾病的风险越高，两者之间存在正相关。最近使用人类精子的生物学研究发现，老年父亲的从头突变增加，并且在老年啮齿动物的精子中发现了高甲基化或低甲基化。精子DNA甲基化异常可能解释ASD发病机制中的跨代效应。然而，与老年男性精子中的这些表观遗传变化相比，生殖细胞遗传倾向的影响在很大程度上是未知的。在这里，我们使用来自13个细胞系的单细胞转录组数据集，包括12个ASD相关的CNV模型和对照，这些细胞系是从小鼠胚胎干细胞进行神经分化的。本研究进行了全面的生物信息学分析，如基因本体论（GO），网络，途径和上游调控分析。通过这些分析，我们确定了几个敏感的途径，如染色质和泛素，除了翻译和氧化磷酸化。我们的研究结果表明，生殖细胞中表观遗传染色体重塑和泛素-蛋白酶体途径的失调可能是随后分化的细胞、精子和卵子的调节剂，是神经发育障碍的危险因素。
Accumulating epidemiological studies have suggested a positive association between advanced paternal age at conception and the increased risk of neurodevelopmental outcomes such as autism spectrum disorder (ASD) in their children. Recent biological studies using human sperm have identified increased de novo mutations in aged fathers, and hyper‐ or hypomethylation has been identified in the sperm from aged rodents. Dysregulation of DNA methylation in sperm may explain the transgenerational effects on the pathogenesis of ASD. However, compared to these epigenetic changes in the sperm of aged males, the effects of inherited predisposition from germ cells are largely unknown. Here, we use single‐cell transcriptome data sets from 13 cell lines, including 12 ASD‐associated CNVs models and control, that are performed neural differentiation from mouse embryonic stem cells. This study performed comprehensive bioinformatic analyses such as gene ontology (GO), network, pathway, and upstream regulator analyses. Through these analyses, we identify several susceptible pathways, such as chromatin and ubiquitin, in addition to translational and oxidative phosphorylation. Our results suggest that dysregulation of epigenetic chromosome remodeling and ubiquitin‐proteasome pathway in the germ cell is a possible modulator for subsequent differentiated cells, sperm, and egg, as a risk factor for the neurodevelopmental disorder.