Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells: RNA-seq

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on a cellular hierarchy reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor- propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance, yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements, and are sufficient to fully reprogram differentiated GBM cells to ‘induced’ TPCs that recapitulate the epigenetic landscape and phenotype of native TPCs. We reconstruct a TF network model that highlights critical interactions and identifies novel therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in a devastating malignancy, provides detailed insight into the underlying gene regulatory programs, and suggests attendant therapeutic strategies. 3'end RNA sequencing

细胞命运决定由主转录因子（master transcription factors, TFs）主导，此类因子通过与顺式调控元件（cis-regulatory elements）结合以调控转录程序。部分恶性肿瘤亦依赖类似正常发育的细胞层级结构，但该结构叠加了潜在的遗传畸变。在胶质母细胞瘤（glioblastoma, GBM）中，一类干细胞样肿瘤增殖细胞（stem-like tumor-propagating cells, TPCs）亚群被认为可驱动肿瘤进展并介导治疗抗性，但其具体机制仍有待进一步解析。本研究鉴定出一组对GBM增殖至关重要的核心神经发育相关转录因子（POU3F2、SOX2、SALL2、OLIG2）。这些转录因子可协同结合并激活TPC特异性调控元件，且足以将分化型GBM细胞完全重编程为"诱导型"TPCs，该诱导细胞可重现天然TPCs的表观遗传图谱与表型。我们构建了转录因子网络模型，该模型可揭示关键相互作用，并识别出可用于清除TPCs的新型治疗靶点。本研究确立了恶性程度极高的恶性肿瘤中发育层级的表观遗传基础，为解析其基因调控程序的潜在机制提供了详细见解，并提出了相应的治疗策略。3'端RNA测序（3'end RNA sequencing）