Núñez-Ríos Diana L, Nagamatsu Sheila T, Martínez-Magaña José Jaime, Montalvo-Ortiz Janitza L
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
National Center of Post-traumatic Stress Disorder, VA CT Healthcare, West Haven, CT, USA.
Yale J Biol Med. 2025 Jun 30;98(2):89-103. doi: 10.59249/VLMZ6974. eCollection 2025 Jun.
Adverse childhood experiences (ACE) can lead to diverse outcomes, ranging from resilience to an increased risk of psychiatric disorders such as anxiety, depression, and posttraumatic stress disorder (PTSD). In mammals, most multiexon genes encode an average of 3.9 protein-coding isoforms, which amplify transcriptomic diversity and potentially exhibit distinct functional characteristics. Recent research has shown long-lasting transcriptomic changes associated with ACE, particularly in immune-related genes. However, differential isoform usage may not be captured when analyses are confined to gene-level expression. To date, no studies have explored isoform-level dysregulation in postmortem brains of individuals exposed to ACEs. Our study investigated transcriptomic dynamics across four prefrontal regions-the dorsolateral (dlPFC), dorsal Anterior Cingulate (dACC), orbitofrontal (OFC), and subgenual prefrontal (sgPFC) cortices-in a cohort of 22 donors with PTSD, comprising 11 with and 11 without ACE history. The OFC exhibited the highest number of differentially expressed genes (DEGs), followed by the sgPFC. Correspondingly, these regions also showed the most pronounced differential isoform usage, or "isoform switching". Notably, our integrated transcriptomic analysis revealed that while was downregulated in the sgPFC among ACE-exposed individuals, its principal isoform (PAQR6-201) showed increased usage. Several genes exhibiting significant isoform switching did not display substantial differential gene expression. Functional pathway analysis revealed that genes with altered expression or isoform usage converged on neurogenesis regulation, with isoform-switching genes specifically enriched in gliogenesis. This study demonstrates that examining differential isoform usage unveils previously unrecognized genes potentially implicated in ACE. Future research should focus on characterizing the functional consequences of isoform-specific up- or downregulation to comprehensively understand transcriptomic dysregulation in complex psychiatric disorders.
童年不良经历（ACE）会导致多种结果，从恢复力到诸如焦虑、抑郁和创伤后应激障碍（PTSD）等精神疾病风险增加。在哺乳动物中，大多数多外显子基因平均编码3.9种蛋白质编码异构体，这增加了转录组多样性，并可能表现出不同的功能特征。最近的研究表明，ACE会导致持久的转录组变化，特别是在免疫相关基因中。然而，当分析局限于基因水平表达时，可能无法捕捉到异构体使用的差异。迄今为止，尚无研究探讨暴露于ACEs个体的死后大脑中异构体水平的失调情况。我们的研究调查了22名患有PTSD的供体队列中四个前额叶区域——背外侧前额叶皮质（dlPFC）、背侧前扣带回（dACC）、眶额皮质（OFC）和膝下前扣带回皮质（sgPFC）——的转录组动态变化，其中11名有ACE病史，11名无ACE病史。OFC表现出最高数量的差异表达基因（DEG），其次是sgPFC。相应地，这些区域也表现出最明显的异构体使用差异，即“异构体切换”。值得注意的是，我们的综合转录组分析显示，虽然在暴露于ACE的个体中，sgPFC中的 下调，但其主要异构体（PAQR6 - 201）的使用增加。几个表现出显著异构体切换的基因并未显示出实质性的差异基因表达。功能通路分析表明，表达改变或异构体使用改变的基因集中在神经发生调节上，异构体切换基因特别富集于神经胶质生成。这项研究表明，检查异构体使用差异揭示了以前未被认识的可能与ACE有关的基因。未来的研究应专注于表征异构体特异性上调或下调的功能后果，以全面了解复杂精神疾病中的转录组失调。
