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 Tomita; Adam 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

doi:10.1038/s41556-023-01093-0

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

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

12 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 language	English (US)
Pages (from-to)	493-507
Number of pages	15
Journal	Nature Cell Biology
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/s41556-023-01093-0
State	Published - Mar 2023

Funding

We thank R. A. DePinho and X. Wu for critically evaluating the manuscript; E. Jane, P. Daniel and D. Yimlamai for their assistance with reagents; J. Dai, X. Lin, X. Lin, T. Wu, M. Wu, J. Hu, K. Peng, Y. Li, Y. Zhang, J. Wang and D. Xing from Central South University, and X. Zheng from UPMC Children’s Hospital of Pittsburgh for their technical support; J. J. Michel, M. L. Mulkeen, M. Airik, K. Prasadan, Y. Wu, A. C. Poholek, W. A. MacDonald and R. Elbakri from the core facilities at the Rangos Research Center for their assistance with flow cytometry, microscopy, mouse imaging and sequencing analyses. We gratefully acknowledge funding support from the Matthew Larson Foundation (to B.H.), the Connor’s Cure Fund from the V Foundation (to B.H.), the Andrew McDonough B+ Foundation (to B.H.), the Scientific Program Fund from the Children’s Hospital of Pittsburgh (to B.H.), NIH/NINDS 1R21NS125218-01 (to B.H.) and NIGMS R35GM133732 (to S.J.H.). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. H.Z. is a University of Pittsburgh-affiliated visiting research scholar supported by CSC and Central South University. We thank R. A. DePinho and X. Wu for critically evaluating the manuscript; E. Jane, P. Daniel and D. Yimlamai for their assistance with reagents; J. Dai, X. Lin, X. Lin, T. Wu, M. Wu, J. Hu, K. Peng, Y. Li, Y. Zhang, J. Wang and D. Xing from Central South University, and X. Zheng from UPMC Children’s Hospital of Pittsburgh for their technical support; J. J. Michel, M. L. Mulkeen, M. Airik, K. Prasadan, Y. Wu, A. C. Poholek, W. A. MacDonald and R. Elbakri from the core facilities at the Rangos Research Center for their assistance with flow cytometry, microscopy, mouse imaging and sequencing analyses. We gratefully acknowledge funding support from the Matthew Larson Foundation (to B.H.), the Connor’s Cure Fund from the V Foundation (to B.H.), the Andrew McDonough B+ Foundation (to B.H.), the Scientific Program Fund from the Children’s Hospital of Pittsburgh (to B.H.), NIH/NINDS 1R21NS125218-01 (to B.H.) and NIGMS R35GM133732 (to S.J.H.). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. H.Z. is a University of Pittsburgh-affiliated visiting research scholar supported by CSC and Central South University.

ASJC Scopus subject areas

Cell Biology

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Zou, H., Poore, B., Brown, E. E., Qian, J., Xie, B., Asimakidou, E., Razskazovskiy, V., Ayrapetian, D., Sharma, V., Xia, S., Liu, F., Chen, A., Guan, Y., Li, Z., Wanggou, S., Saulnier, O., Ly, M., Fellows-Mayle, W., Xi, G., ... Hu, B. (2023). A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis. Nature Cell Biology, 25(3), 493-507. https://doi.org/10.1038/s41556-023-01093-0

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

doi = "10.1038/s41556-023-01093-0",

language = "English (US)",

volume = "25",

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Zou, H, Poore, B, Brown, EE, Qian, J, Xie, B, Asimakidou, E, Razskazovskiy, V, Ayrapetian, D, Sharma, V, Xia, S, Liu, F, Chen, A, Guan, Y, Li, Z, Wanggou, S, Saulnier, O, Ly, M, Fellows-Mayle, W, Xi, G, Tomita, T, Resnick, AC, Mack, SC, Raabe, EH, Eberhart, CG, Sun, D, Stronach, BE, Agnihotri, S, Kohanbash, G, Lu, S, Herrup, K, Rich, JN, Gittes, GK, Broniscer, A, Hu, Z, Li, X, Pollack, IF, Friedlander, RM, Hainer, SJ, Taylor, MD & Hu, B 2023, 'A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis', Nature Cell Biology, vol. 25, no. 3, pp. 493-507. https://doi.org/10.1038/s41556-023-01093-0

TY - JOUR

T1 - A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis

AU - Zou, Han

AU - Poore, Bradley

AU - Brown, Emily E.

AU - Qian, Jieqi

AU - Xie, Bin

AU - Asimakidou, Evridiki

AU - Razskazovskiy, Vladislav

AU - Ayrapetian, Deanna

AU - Sharma, Vaibhav

AU - Xia, Shunjin

AU - Liu, Fei

AU - Chen, Apeng

AU - Guan, Yongchang

AU - Li, Zhengwei

AU - Wanggou, Siyi

AU - Saulnier, Olivier

AU - Ly, Michelle

AU - Fellows-Mayle, Wendy

AU - Xi, Guifa

AU - Tomita, Tadanori

AU - Resnick, Adam C.

AU - Mack, Stephen C.

AU - Raabe, Eric H.

AU - Eberhart, Charles G.

AU - Sun, Dandan

AU - Stronach, Beth E.

AU - Agnihotri, Sameer

AU - Kohanbash, Gary

AU - Lu, Songjian

AU - Herrup, Karl

AU - Rich, Jeremy N.

AU - Gittes, George K.

AU - Broniscer, Alberto

AU - Hu, Zhongliang

AU - Li, Xuejun

AU - Pollack, Ian F.

AU - Friedlander, Robert M.

AU - Hainer, Sarah J.

AU - Taylor, Michael D.

AU - Hu, Baoli

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

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JF - Nature Cell Biology

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

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