PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells [ChIP-Seq]

Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the regulation of pituitary transcription factors Hesx1 and Pit1. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome wide analysis of PROP1 DNA binding and effects on gene expression in mutant tissues, isolated stem cells and engineered cell lines. We determined that PROP1 is essential for maintaining proliferation of stem cells and stimulating them to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to and represses claudin 23, characteristic of epithelial cells, and it activates EMT inducer genes: Zeb2, Notch2 and Gli2. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.

PROP1（配对样同源盒基因1）突变是人类垂体功能减退症最常见的致病原因，因此从治疗视角阐明其作用机制具有极高的科研与转化价值。目前学界对PROP1在垂体中的作用认知，仅局限于其对垂体转录因子Hesx1与Pit1的调控。为阐明完整的PROP1依赖型基因调控网络，我们开展了全基因组层面的分析，探究PROP1的DNA结合特性，以及其在突变组织、分离干细胞与工程化细胞系中对基因表达的调控效应。研究证实，PROP1对于维持干细胞增殖、诱导其发生上皮-间质转化（epithelial to mesenchymal transition, EMT）样过程以满足细胞迁移与分化的必要条件至关重要。基因组谱分析显示，PROP1可结合并抑制上皮细胞标志性的紧密连接蛋白23（claudin 23）的表达，同时激活EMT诱导基因Zeb2、Notch2与Gli2。本研究结果将PROP1鉴定为垂体干细胞分化过程中的核心转录调控因子。