Integrative epigenomic analyses of early-life hypothalamic response to augmented maternal care [BiSulfite-seq]

The quality of maternal care in early-life plays a crucial role in mammalian neurodevelopment. Augmented maternal care (AMC) is a well-established rodent model of enhanced neonatal care. Rats that have undergone AMC have improved stress resilience and cognition compared with rats that have experienced normal levels of maternal care or adverse neonatal stress. However, the epigenomic basis of long-lived responses to AMC has not been previously explored. Thus, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to assess DNA cytosine methylation, gene expression, and miRNA expression, respectively. The integrated results identify a suite of 20 prioritized candidates impacted by AMC. Overall, these results identified AMC-induced regulatory differences in genes related to neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation in addition to the expected stress response genes. Together, these unbiased results represent a key progression in understanding the complex mechanisms underlying the early-life mechanisms for AMC programming stress resiliency.生命早期的母育照料质量对哺乳动物的神经发育至关重要。增强型母育照料（Augmented Maternal Care, AMC）是一种被广泛验证的啮齿类动物新生期照料增强模型。与接受常规母育照料或遭遇新生期不良应激的大鼠相比，经过AMC处理的大鼠应激韧性与认知能力均得到显著改善。然而，此前尚未有研究探讨AMC所诱导的长期应答的表观基因组学基础。为此，本研究采用全基因组亚硫酸氢盐测序（Whole-Genome Bisulfite Sequencing, WGBS）、RNA测序（RNA-sequencing, RNA-seq）以及多重微RNA（microRNA, miRNA）检测技术，分别评估DNA胞嘧啶甲基化水平、基因表达水平与miRNA表达水平。整合分析结果筛选出20个受AMC调控的优先候选靶点。整体而言，除预期的应激响应基因外，本研究还发现AMC可诱导与神经传递、神经发育、蛋白质合成以及氧化磷酸化相关基因的表达调控差异。综上，这些无偏分析结果为理解AMC通过生命早期机制编程应激韧性的复杂调控机制提供了关键进展。