Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal cells and committed adrenergic cells can interconvert and resemble cells from different lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic cells identified a distinct super-enhancer landscape and super-enhancer-associated TF network for each cell type. Expression of the mesenchymal TF PRRX1 could reprogram the super-enhancer and mRNA landscapes of adrenergic cells toward a mesenchymal state. Mesenchymal cells were more chemoresistant in vitro and were enriched in post-therapy and relapse tumors. Two super-enhancer-associated TF networks, which probably mediate lineage control in normal development, thus dominate epigenetic control of neuroblastoma and shape intratumoral heterogeneity.

中文翻译：

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神经母细胞瘤由两个与超级增强子相关的分化状态组成。

神经母细胞瘤和其他小儿肿瘤显示出很少的基因突变，这引起了人们对其表观遗传调控的兴趣。几种肿瘤类型包括表型趋异细胞，类似于来自不同谱系发育阶段的细胞。已经提出，超增强子相关转录因子（TF）网络是谱系同一性的基础，但是这些增强子在肿瘤内异质性中的作用尚不清楚。在这里，我们显示大多数神经母细胞瘤包括两种类型的具有不同基因表达谱的肿瘤细胞。未分化的间充质细胞和定型肾上腺能细胞可以相互转化并类似于来自不同谱系分化阶段的细胞。对间充质和肾上腺素能细胞的同基因对的ChIP-seq分析确定了每种细胞类型的独特的超级增强子景观和超级增强子相关的TF网络。间质TF PRRX1的表达可以将肾上腺素能细胞的超增强子和mRNA景观重新编程为间质状态。间充质细胞在体外具有更高的化学耐药性，并在治疗后和复发性肿瘤中富集。两个可能在正常发育中介导谱系控制的超增强子相关的TF网络，从而主导了神经母细胞瘤的表观遗传控制，并塑造了瘤内异质性。间充质细胞在体外具有更高的化学耐药性，并在治疗后和复发性肿瘤中富集。两个可能在正常发育中介导谱系控制的超增强子相关的TF网络，从而主导了神经母细胞瘤的表观遗传控制，并塑造了瘤内异质性。间充质细胞在体外具有更高的化学耐药性，并在治疗后和复发性肿瘤中富集。两个可能在正常发育中介导谱系控制的超增强子相关的TF网络，从而主导了神经母细胞瘤的表观遗传控制，并塑造了瘤内异质性。