儿童松果母细胞瘤(PBs)是罕见且具有Ⅳ级组织学的侵略性肿瘤。虽然已经确定了一些致癌驱动因子，包括RB1和DICER1的生殖细胞突变，但在PB发病和进展中，表观遗传失调和顺式调节区域的作用仍不明确。在这里，我们从CCND1驱动PB的小鼠模型的松果体组织中生成了覆盖PB发病和进展的关键时间点的全基因组基因表达、染色质可及性和H3K27ac轮廓。我们鉴定了PB特异性增强子和超增强子，并发现在某些情况下，可达到基因组动态先于转录组变化，这是肿瘤进展领域未被充分探索的特征。在PB进展过程中，新获得的缺乏H3K27ac信号的开放染色质区域变得富含抑制状态元件，并寄宿着如HINFP、GLI2和YY1等转录因子的调制位点。拷贝数变异分析确定了特定于肿瘤形成阶段的缺失事件，影响到组蛋白基因簇和Gas1、生长抑制特定基因等。基因集富集分析和基因表达特征定位所使用的模型位置靠近人类PB样本，表明我们研究结果在探索PB治疗和管理的新途径中具有潜力。总的来说，这项研究报道了PB中首个时序和体内顺式调节、表达和可访问性图谱。©2023 Idriss et al.；由Cold Spring Harbor实验室出版。

Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations in RB1 and DICER1, the role of epigenetic deregulation and cis-regulatory regions in PB pathogenesis and progression is largely unknown. Here, we generated genome-wide gene expression, chromatin accessibility, and H3K27ac profiles covering key time points of PB initiation and progression from pineal tissues of a mouse model of CCND1-driven PB. We identified PB-specific enhancers and super-enhancers, and found that in some cases, the accessible genome dynamics precede transcriptomic changes, a characteristic that is underexplored in tumor progression. During progression of PB, newly acquired open chromatin regions lacking H3K27ac signal become enriched for repressive state elements and harbor motifs of repressor transcription factors like HINFP, GLI2, and YY1. Copy number variant analysis identified deletion events specific to the tumorigenic stage, affecting, among others, the histone gene cluster and Gas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples, showing the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivo cis-regulatory, expression, and accessibility maps in PB.© 2023 Idriss et al.; Published by Cold Spring Harbor Laboratory Press.