Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.

超级增强子 (SE) 驱动的转录因子 (TF) 的时间调节是正常发育程序的基础。神经母细胞瘤 (NB) 是由于交感肾上腺祖细胞无法退出自我更新程序并最终分化而引起的。为了识别驱动 TF 调节因子的 SE，我们使用全反式视黄酸 (ATRA) 来诱导 NB 生长停滞和分化。时程 H3K27ac ChIP-seq 和 RNA-seq 揭示了 ATRA 协调的 SE 波。 ATRA 降低的 SE 与干细胞发育有关（MYCN、GATA3、SOX11）。 CRISPR-Cas9 和 siRNA 在体外和体内验证 SOX11 依赖性。使用 dCAS9-KRAB沉默SOX11 SE 可减少SOX11 mRNA 并抑制细胞生长。其他 TF 在 ATRA 治疗的第 2、4 和 8 天按顺序波激活，调节神经发育（GATA2和SOX4）。使用 dCAS9-KRAB沉默获得的SOX4 SE 会降低SOX4表达并减弱 ATRA 诱导的分化基因。我们的研究确定了 NB 自我更新的致癌谱系驱动因素和对于实施分化计划至关重要的 TF。