Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice

Generating effective therapies for neurodevelopmental disorders has remained elusive. An emerging drug discovery approach for neurodevelopmental disorders is to characterize transcriptome wide dysregulation in an appropriate model system and screen therapeutics based on their capacity to restore functionally relevant expression patterns. We characterized transcriptomic dysregulation in a human model of HNRNPU-related disorder to explore the potential of such a paradigm. We identified widespread dysregulation in functionally relevant pathways and then compared dysregulation in a human model to transcriptomic differences in embryonic and perinatal mice to determine whether dysregulation in an in vitro human model is partially replicated in an in vivo model of HNRNPU-related disorder. Strikingly, we find enrichment of co-dysregulation between 45-day-old human organoids and embryonic, but not perinatal, mice from distinct models of HNRNPU-related disorder. Thus, hnRNPU deficient human organoids may only be suitable to model transcriptional dysregulation in certain cell types within a specific developmental time window.针对神经发育障碍开发有效疗法始终是一项极具挑战性的难题。当前针对神经发育障碍的新兴药物研发策略，是在合适的模型系统中表征全转录组水平的失调情况，并基于疗法恢复功能相关表达模式的能力来筛选候选药物。本研究通过对HNRNPU相关障碍（HNRNPU-related disorder）的人类模型进行全转录组失调表征，以探究该研发范式的应用潜力。我们在功能相关通路中发现了广泛的转录失调现象，随后将人类模型中的失调情况与胚胎期和围产期小鼠的转录组差异进行比对，以验证体外人类模型中的失调现象能否在HNRNPU相关障碍的体内模型中得到部分重现。令人瞩目的是，我们发现来自不同HNRNPU相关障碍模型的45天龄人类类器官与胚胎期小鼠之间存在共失调富集现象，而与围产期小鼠则无此现象。由此可见，hnRNPU缺陷型人类类器官或许仅适用于模拟特定发育时间窗口内特定细胞类型的转录失调情况。