Table 1_Analysis of microRNA-transcript regulatory networks in the hippocampus of the BTBR mouse model of autism.xlsx

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with unknown etiology. Currently, the role of post-transcriptional mechanisms in ASD remains unclear. microRNAs (miRNAs) are small non-coding regulatory RNAs that mediate mRNA destabilization and/or translational repression. To investigate the potential role of miRNAs in ASD, we performed miRNA expression profiling in the hippocampus of the BTBR ASD mouse model and age-matched C57BL/6 J mice. Alongside, we analyzed the BTBR hippocampal transcriptomic profile to identify differentially expressed transcripts (DETs). By integrating differentially expressed miRNA (DEmiRNA) and DET lists, we discovered mRNA transcripts that are putative targets of BTBR DEmiRNAs and exhibit an anti-correlated differential expression in the BTBR hippocampus. These interactions suggest potential regulatory networks related to gene transcription regulation, and synaptic structure and function relevant for ASD. These include miR-200 family members, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, and the experimentally validated target, the transcription factor Zeb2. Moreover, we identified a set of non-canonical interactions characterized by extensive pairing between BTBR DEmiRNAs and DETs, potentially triggering target-directed miRNA degradation (TDMD). Our findings support a role for miRNA dysregulation in the pathophysiology of ASD.

孤独症谱系障碍（Autism spectrum disorder, ASD）是一类病因未明的异质性神经发育疾病。目前，转录后调控机制在ASD发病中的作用仍不明确。微小RNA（microRNAs, miRNAs）是一类小型非编码调控RNA，可介导mRNA降解和/或翻译抑制。为探究miRNAs在ASD中的潜在作用，我们对BTBR ASD小鼠模型以及年龄匹配的C57BL/6J小鼠的海马体进行了miRNA表达谱分析。同时，我们分析了BTBR小鼠海马体的转录组谱，以鉴定差异表达转录本（differentially expressed transcripts, DETs）。通过整合差异表达miRNA（differentially expressed miRNA, DEmiRNA）与DETs列表，我们发现了作为BTBR DEmiRNA潜在靶标、且在BTBR小鼠海马体中呈现负相关差异表达的mRNA转录本。这些相互作用提示了与ASD相关的基因转录调控、突触结构与功能相关的潜在调控网络。其中包括miR-200家族成员：miR-200a-3p、miR-200b-3p、miR-200c-3p以及miR-429，以及经实验验证的靶标——转录因子Zeb2。此外，我们还鉴定出一类以BTBR DEmiRNA与DETs间广泛配对为特征的非经典相互作用，这类相互作用可能触发靶标导向的miRNA降解（target-directed miRNA degradation, TDMD）。本研究结果支持miRNA失调参与ASD病理生理过程这一观点。