SOX1 is required for the specification of rostral hindbrain neural progenitor cells from human embryonic stem cells

Region-specific neural progenitor cells (NPCs) can be generated from human embryonic stem cells (hESCs) through modulating signaling pathways. However, how intrinsic transcriptional factors contribute to the neural regionalization are not well characterized. Here, we generate region-specific NPCs from hESCs and find that SOX1 is highly expressed in NPCs with the rostral hindbrain identity. Moreover, we find that OTX2 inhibits SOX1 expression, displaying exclusive expression between the two factors. Furthermore, SOX1 knockout (KO) leads to up-regulation of midbrain genes and down-regulation of rostral hindbrain genes, indicating that SOX1 is necessary for specification of rostral hindbrain NPCs. Our SOX1 ChIP-sequencing analysis reveals that SOX1 binds to the distal region of GBX2 to activate its expression. Overexpression of GBX2 largely abrogates SOX1-KO induced aberrant gene expression. Taken together, this study uncovers previously unappreciated role of SOX1 in early neural regionalization and provides new information for the precise control of the OTX2/GBX2 interface.

区域特异性神经前体细胞（neural progenitor cells, NPCs）可通过调控信号通路，从人类胚胎干细胞（human embryonic stem cells, hESCs）中诱导产生。然而，内源性转录因子如何参与神经区域化进程，目前尚未得到充分阐明。本研究从hESCs中诱导获得区域特异性神经前体细胞，并发现SOX1在具有吻端后脑细胞身份的NPCs中呈高表达。此外，本研究发现OTX2可抑制SOX1的表达，二者呈现互斥的表达模式。进一步实验显示，SOX1敲除（knockout, KO）会导致中脑相关基因的上调表达以及吻端后脑相关基因的下调表达，表明SOX1对于吻端后脑NPCs的细胞命运特化是必需的。本研究的SOX1染色质免疫共沉淀测序（ChIP-sequencing）分析显示，SOX1可结合至GBX2的远端调控区域并激活其转录。过表达GBX2可在很大程度上逆转SOX1敲除所诱导的异常基因表达。综上，本研究揭示了SOX1在早期神经区域化中此前未被认知的重要作用，并为OTX2与GBX2之间相互作用界面的精准调控提供了新的理论依据。