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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 Disabled 1 (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 homologue 2 (EZH2) and nuclear factor I X (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.

Original languageEnglish (US)
Pages (from-to)493-507
Number of pages15
JournalNature Cell Biology
Volume25
Issue number3
DOIs
StatePublished - Mar 2023

ASJC Scopus subject areas

  • Cell Biology

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