Abstract：
BACKGROUND: Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB).
METHODS: The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing.
RESULTS: The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2 and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB.
CONCLUSIONS: Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of NB susceptibility gene ALK.
METHODS: The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing.
RESULTS: The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2 and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB.
CONCLUSIONS: Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of NB susceptibility gene ALK.
摘要：
背景：超级增强子（SE）通常控制关键癌基因的表达，并在癌症的发生和发展中起重要作用。关注癌症中SE异常调控的基因可能是理解发病机制的新策略。在这次调查中,我们在神经母细胞瘤(NB)中发现了一个以前未报道的SE驱动基因IRF2BP2.
方法：在公共数据库和临床样本中检测IRF2BP2的表达和预后价值。通过体内和体外功能丧失实验评价IRF2BP2对NB细胞生长和凋亡的影响。通过染色质调控区和转录组测序研究IRF2BP2的分子机制。
结果：IRF2BP2的持续高表达是由NB主转录因子MYCN建立的新型SE的激活引起的，MEIS2和HAND2，它们形成了一个新的复合物，调节与NB细胞群增殖相关的基因网络。我们还观察到在IRF2BP2的结合位点处AP-1家族的显著富集。值得注意的是,在NB小区中，AP-1在塑造染色质可及性景观中起着关键作用，从而暴露IRF2BP2的结合位点。这种协调作用使AP-1和IRF2BP2能够协同刺激NB易感基因ALK的表达，从而保持NB的高度增殖表型特征。
结论：我们的发现表明，SE驱动的IRF2BP2可以通过调节NB易感基因ALK的染色质可及性与AP-1结合来维持肿瘤细胞的存活。
方法：在公共数据库和临床样本中检测IRF2BP2的表达和预后价值。通过体内和体外功能丧失实验评价IRF2BP2对NB细胞生长和凋亡的影响。通过染色质调控区和转录组测序研究IRF2BP2的分子机制。
结果：IRF2BP2的持续高表达是由NB主转录因子MYCN建立的新型SE的激活引起的，MEIS2和HAND2，它们形成了一个新的复合物，调节与NB细胞群增殖相关的基因网络。我们还观察到在IRF2BP2的结合位点处AP-1家族的显著富集。值得注意的是,在NB小区中，AP-1在塑造染色质可及性景观中起着关键作用，从而暴露IRF2BP2的结合位点。这种协调作用使AP-1和IRF2BP2能够协同刺激NB易感基因ALK的表达，从而保持NB的高度增殖表型特征。
结论：我们的发现表明，SE驱动的IRF2BP2可以通过调节NB易感基因ALK的染色质可及性与AP-1结合来维持肿瘤细胞的存活。
