PPARG-centric transcriptional re-wiring during differentiation of human trophoblast stem cells into extravillous trophoblasts [RNA-seq]

Peroxisome Proliferator-Activated Receptor gamma (PPARG) is a nuclear receptor transcription factor critical for placental development. Using human trophoblast stem cells (TSCs) and their differentiation into extravillous trophoblasts (EVTs) as a model, we show that PPARG is required for both TSC self-renewal and EVT differentiation. ChIP-seq revealed that PPARG occupies distinct sets of regulatory elements in TSCs and EVTs, forming cell-type specific transcriptional networks. Integration with other trophoblast-specific transcription factors suggests that PPARG participates in transcriptional re-wiring during EVT differentiation. Functionally, activation of PPARG promotes EVT invasion, suggesting a potential connection between PPARG signaling and placental pathologies such as placenta accreta. These findings highlight context-specific roles of PPARG in modulating gene expression and cell behavior during human trophoblast development. Overall design: RNA-seq was conducted on human trophoblast stem cells (TSCs) and extravillous trophoblasts (EVTs) at day 8 (EVTd8) under various conditions.

过氧化物酶体增殖物激活受体γ（Peroxisome Proliferator-Activated Receptor gamma, PPARG）是一类对胎盘发育至关重要的核受体转录因子。本研究以人滋养层干细胞（trophoblast stem cells, TSCs）及其向绒毛外滋养层细胞（extravillous trophoblasts, EVTs）的分化模型为研究对象，证实PPARG对于TSCs的自我更新以及EVTs的分化均不可或缺。染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）结果显示，PPARG在TSCs与EVTs中结合的调控元件集存在显著差异，并进而形成细胞类型特异性的转录调控网络。通过与其他滋养层细胞特异性转录因子的数据整合分析，本研究提示PPARG在EVTs分化过程中参与了转录重编程事件。功能实验表明，激活PPARG可促进EVTs的侵袭能力，这提示PPARG信号通路与胎盘植入（placenta accreta）等胎盘病理状态存在潜在关联。本研究结果凸显了PPARG在人滋养层细胞发育过程中，依据细胞微环境调控基因表达与细胞行为的特异性功能。实验设计概述：在多种培养条件下，分别对人滋养层干细胞（TSCs）以及分化第8天的绒毛外滋养层细胞（EVTd8）开展了RNA测序（RNA Sequencing, RNA-seq）实验。