美国匹兹堡大学Baoli Hu研究团队发现由SMARCD3-DAB1-Reelin信号介导的神经发育表观遗传学程序被劫持以促进髓母细胞瘤（MB）转移。2023年2月27日，国际知名学术期刊《自然—细胞生物学》发表了这一成果。

他们发现了一个神经发育表观基因组程序，该程序被劫持以诱导MB转移性播散。使用新生成的数据对集成的公开数据集进行无监督分析表明，SMARCD3（也称为BAF60C）通过协调DAB1位点的顺式调节元件来调节Purkinje细胞迁移和MB转移中DAB1介导的Reelin信号传导。他们进一步确定一组核心转录因子，即 zeste 同系物 2 （EZH2） 和核因子 I X （NFIX） 的增强子，与 SMARCD3 位点的顺式调节元件协调形成染色质中枢以控制发育中的小脑和转移性 MB 中的 SMARCD3 表达。增加的SMARCD3表达激活Reelin-DAB1介导的Src激酶信号传导，导致对Src抑制的MB应答。这些数据加深了人们对神经发育编程如何影响疾病进展的理解，并为MB患者提供了潜在的治疗选择。

据悉，髓母细胞瘤是最常见的胚胎肿瘤类型，异常神经发育与MB的肿瘤侵袭性有何关系，仍不清楚。

附：英文原文

Title: A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis

Author: Zou, Han, Poore, Bradley, Brown, Emily E., Qian, Jieqi, Xie, Bin, Asimakidou, Evridiki, Razskazovskiy, Vladislav, Ayrapetian, Deanna, Sharma, Vaibhav, Xia, Shunjin, Liu, Fei, Chen, Apeng, Guan, Yongchang, Li, Zhengwei, Wanggou, Siyi, Saulnier, Olivier, Ly, Michelle, Fellows-Mayle, Wendy, Xi, Guifa, Tomita, Tadanori, Resnick, Adam C., Mack, Stephen C., Raabe, Eric H., Eberhart, Charles G., Sun, Dandan, Stronach, Beth E., Agnihotri, Sameer, Kohanbash, Gary, Lu, Songjian, Herrup, Karl, Rich, Jeremy N., Gittes, George K., Broniscer, Alberto, Hu, Zhongliang, Li, Xuejun, Pollack, Ian F., Friedlander, Robert M., Hainer, Sarah J., Taylor, Michael D., Hu, Baoli

Issue&Volume: 2023-02-27

Abstract: How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue2 (EZH2) and nuclear factorIX (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin–DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.

DOI: 10.1038/s41556-023-01093-0

Source: https://www.nature.com/articles/s41556-023-01093-0