Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

Abstract: Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. In this study, we used single-cell and cell-type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics- with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GCs influenced lineage specification primarily by priming the inhibitory neuron lineage through key transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.摘要：人类大脑发育这一严格调控的生理过程发生紊乱时，会提升脑部及精神类疾病的患病风险。目前学界已明确遗传因素在这类疾病发病中的作用，但针对其重要环境影响因素的分子、细胞层面研究仍较为匮乏。本研究采用单细胞及细胞类型特异性技术，探究了产前环境风险介质糖皮质激素（glucocorticoid, GC）暴露对无定向诱导的人类神经类器官基因调控与细胞谱系特化的影响。我们对神经分化过程中慢性糖皮质激素暴露的转录响应进行了系统表征，并通过整合单细胞转录组（single-cell transcriptomics）与染色质可及性（chromatin accessibility）数据，解析了其潜在的基因调控网络。研究发现，慢性糖皮质激素暴露会引发持久的细胞类型特异性转录变化，其中涵盖自闭症风险基因及多种与神经发育相关的转录因子（transcription factors）。慢性糖皮质激素主要通过PBX3等关键转录因子启动抑制性神经元谱系的特化，进而调控细胞谱系分化进程。本研究为遗传与环境风险因素通过改变细胞谱系特化这一共同机制产生协同影响提供了实验证据。