Dominant clones leverage developmental epigenomic states to drive ependymoma

Alisha S. Kardian; Hua Sun; Siri Ippagunta; Nicholas Laboe; Srinidhi Varadharajan; Kwanha Yu; Hsiao Chi Chen; Erik Emanus; Tuyu Zheng; Riley M. Deneen; Jon P. Connelly; Yong Dong Wang; Jiangshan Zhan; Hengxi Liu; Kimberley Lowe; Taylor Bugbee; Rakesh Pathak; Amanda Bland; Sanya Mehta; Sophie Cochiolo; Amir Arabzade; Blake Holcomb; Kaitlin M. Budd; Gabriele Kembuan; Tristen Wright; Emma Caesar; Maxwell Park; Amelia Hancock; David Gee; Joel Murdoch; Yi Xiao; Samuel K. McBrayer; Thomas E. Merchant; Jun Qi; Adam D. Durbin; Lindsay A. Schwarz; Li Wang; Andrew M. Donson; Nicholas K. Foreman; Sameer Agnihotri; Alfonso Lavado; Suzanne J. Baker; David W. Ellison; Hyun Kyoung Lee; Shondra M. Pruett-Miller; Kelsey C. Bertrand; Benjamin Deneen; Stephen C. Mack

doi:10.1038/s41586-026-10270-8

Dominant clones leverage developmental epigenomic states to drive ependymoma

Alisha S. Kardian, Hua Sun, Siri Ippagunta, Nicholas Laboe, Srinidhi Varadharajan, Kwanha Yu, Hsiao Chi Chen, Erik Emanus, Tuyu Zheng, Riley M. Deneen, Jon P. Connelly, Yong Dong Wang, Jiangshan Zhan, Hengxi Liu, Kimberley Lowe, Taylor Bugbee, Rakesh Pathak, Amanda Bland, Sanya Mehta, Sophie CochioloAmir Arabzade, Blake Holcomb, Kaitlin M. Budd, Gabriele Kembuan, Tristen Wright, Emma Caesar, Maxwell Park, Amelia Hancock, David Gee, Joel Murdoch, Yi Xiao, Samuel K. McBrayer, Thomas E. Merchant, Jun Qi, Adam D. Durbin, Lindsay A. Schwarz, Li Wang, Andrew M. Donson, Nicholas K. Foreman, Sameer Agnihotri, Alfonso Lavado, Suzanne J. Baker, David W. Ellison, Hyun Kyoung Lee, Shondra M. Pruett-Miller, Kelsey C. Bertrand, Benjamin Deneen, Stephen C. Mack

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

Abstract

ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.

Original language	English
Pages (from-to)	1027-1037
Number of pages	31
Journal	Nature
Volume	652
Early online date	25 Mar 2026
DOIs	https://doi.org/10.1038/s41586-026-10270-8
Publication status	Published - 23 Apr 2026
Externally published	Yes

Data Availability Statement

Data generated for this study are available at the Gene Expression Omnibus (accessions GSE269937, GSE314803, GSE314599 and GSE314911). All other data are available in the manuscript or in Supplementary Figures or Tables 1–5. All data needed to evaluate the conclusions of the paper are present in the paper and Extended Data Figs. 1–10.

Funding

This study was supported by a NCI Cancer Center Support Grant, P30 CA021765, St. Jude Children’s Research Hospital Research Collaborative on Transcription Regulation in Pediatric Cancer Grant, St Jude Children’s Research Hospital institutional funds, and Alex’s Lemonade Stand Foundation ‘A’ Award; and by P01CA298963-01, R01NS128184, R01CA280203, R01CA284455, U01CA281823, DOD-IDEA (CA220510) and a DOD-IMPACT (CA220247) award (to S.C.M.). S.C.M. is supported by funding from the National Brain Tumor Society and CERN Foundation. This work was also supported by US National Institutes of Health grants R35-NS132230, R01-NS124093, R01-CA223388 to B.D. and K99CA277576 to Y.X.; National Cancer Institute Cancer Target Discovery and Development grant U01-CA217842 to B.D.; and grants from the Helis Medical Research Foundation (to H.K.L.), the Ependymoma Research Foundation (to J.Q.), the NIH/NINDS (2R01NS110859 and R01NS126287 to H.K.L.), the Human Frontier Science Program (LT0018/2022-L to Y.X.), and the Wallace Endowment established by an anonymous donor and the Petrello family (to H.K.L.). Further support was provided by the NMSS postdoctoral fellowship (FG-2407-43793 to J.Z.), P01CA096832 (S.J.B.) and F31CA265285 (K.M.B.). We acknowledge J. Norrie and the Single Cell Core for training and allowing us to use their Chromium machine, and the Christian Mayer laboratory for their generous donation of TrackerSeq plasmids and for guiding us through the initial optimization experiments. We thank A. Ansari and his team for helping us with the application and analysis of the CSI technology to study ZR, and C. Schuurmans for her generous donation of Plagl-related plasmids and valuable advice. Several other St. Jude core facilities were instrumental in this work, including the Cell and Tissue Imaging Center (CTIC), the Hartwell Center for Bioinformatics & Biotechnology (funded partially by ALSAC, NCI grant P30 CA021765), Robert Throm and the St. Jude Vector Laboratory Shared Resource (funded partially by ALSAC), the Center for Advanced Genome Engineering (CAGE; funded partially by ALSAC, NCI grant P30 CA021765) and the Department of Developmental Neurobiology Flow Cytometry Lab.

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Kardian, A. S., Sun, H., Ippagunta, S., Laboe, N., Varadharajan, S., Yu, K., Chen, H. C., Emanus, E., Zheng, T., Deneen, R. M., Connelly, J. P., Wang, Y. D., Zhan, J., Liu, H., Lowe, K., Bugbee, T., Pathak, R., Bland, A., Mehta, S., ... Mack, S. C. (2026). Dominant clones leverage developmental epigenomic states to drive ependymoma. Nature, 652, 1027-1037. https://doi.org/10.1038/s41586-026-10270-8

Kardian, AS, Sun, H, Ippagunta, S, Laboe, N, Varadharajan, S, Yu, K, Chen, HC, Emanus, E, Zheng, T, Deneen, RM, Connelly, JP, Wang, YD, Zhan, J, Liu, H, Lowe, K, Bugbee, T, Pathak, R, Bland, A, Mehta, S, Cochiolo, S, Arabzade, A, Holcomb, B, Budd, KM, Kembuan, G, Wright, T, Caesar, E, Park, M, Hancock, A, Gee, D, Murdoch, J, Xiao, Y, McBrayer, SK, Merchant, TE, Qi, J, Durbin, AD, Schwarz, LA, Wang, L, Donson, AM, Foreman, NK, Agnihotri, S, Lavado, A, Baker, SJ, Ellison, DW, Lee, HK, Pruett-Miller, SM, Bertrand, KC, Deneen, B & Mack, SC 2026, 'Dominant clones leverage developmental epigenomic states to drive ependymoma', Nature, vol. 652, pp. 1027-1037. https://doi.org/10.1038/s41586-026-10270-8

@article{b62db165753743bf85b02270e55fd8d8,

title = "Dominant clones leverage developmental epigenomic states to drive ependymoma",

abstract = "ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression. ",

author = "Kardian, \{Alisha S.\} and Hua Sun and Siri Ippagunta and Nicholas Laboe and Srinidhi Varadharajan and Kwanha Yu and Chen, \{Hsiao Chi\} and Erik Emanus and Tuyu Zheng and Deneen, \{Riley M.\} and Connelly, \{Jon P.\} and Wang, \{Yong Dong\} and Jiangshan Zhan and Hengxi Liu and Kimberley Lowe and Taylor Bugbee and Rakesh Pathak and Amanda Bland and Sanya Mehta and Sophie Cochiolo and Amir Arabzade and Blake Holcomb and Budd, \{Kaitlin M.\} and Gabriele Kembuan and Tristen Wright and Emma Caesar and Maxwell Park and Amelia Hancock and David Gee and Joel Murdoch and Yi Xiao and McBrayer, \{Samuel K.\} and Merchant, \{Thomas E.\} and Jun Qi and Durbin, \{Adam D.\} and Schwarz, \{Lindsay A.\} and Li Wang and Donson, \{Andrew M.\} and Foreman, \{Nicholas K.\} and Sameer Agnihotri and Alfonso Lavado and Baker, \{Suzanne J.\} and Ellison, \{David W.\} and Lee, \{Hyun Kyoung\} and Pruett-Miller, \{Shondra M.\} and Bertrand, \{Kelsey C.\} and Benjamin Deneen and Mack, \{Stephen C.\}",

year = "2026",

month = apr,

day = "23",

doi = "10.1038/s41586-026-10270-8",

language = "English",

volume = "652",

pages = "1027--1037",

journal = "Nature",

issn = "1476-4687",

publisher = "Nature Research",

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TY - JOUR

T1 - Dominant clones leverage developmental epigenomic states to drive ependymoma

AU - Kardian, Alisha S.

AU - Sun, Hua

AU - Ippagunta, Siri

AU - Laboe, Nicholas

AU - Varadharajan, Srinidhi

AU - Yu, Kwanha

AU - Chen, Hsiao Chi

AU - Emanus, Erik

AU - Zheng, Tuyu

AU - Deneen, Riley M.

AU - Connelly, Jon P.

AU - Wang, Yong Dong

AU - Zhan, Jiangshan

AU - Liu, Hengxi

AU - Lowe, Kimberley

AU - Bugbee, Taylor

AU - Pathak, Rakesh

AU - Bland, Amanda

AU - Mehta, Sanya

AU - Cochiolo, Sophie

AU - Arabzade, Amir

AU - Holcomb, Blake

AU - Budd, Kaitlin M.

AU - Kembuan, Gabriele

AU - Wright, Tristen

AU - Caesar, Emma

AU - Park, Maxwell

AU - Hancock, Amelia

AU - Gee, David

AU - Murdoch, Joel

AU - Xiao, Yi

AU - McBrayer, Samuel K.

AU - Merchant, Thomas E.

AU - Qi, Jun

AU - Durbin, Adam D.

AU - Schwarz, Lindsay A.

AU - Wang, Li

AU - Donson, Andrew M.

AU - Foreman, Nicholas K.

AU - Agnihotri, Sameer

AU - Lavado, Alfonso

AU - Baker, Suzanne J.

AU - Ellison, David W.

AU - Lee, Hyun Kyoung

AU - Pruett-Miller, Shondra M.

AU - Bertrand, Kelsey C.

AU - Deneen, Benjamin

AU - Mack, Stephen C.

PY - 2026/4/23

Y1 - 2026/4/23

N2 - ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.

AB - ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.

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U2 - 10.1038/s41586-026-10270-8

DO - 10.1038/s41586-026-10270-8

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AN - SCOPUS:105034169222

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VL - 652

SP - 1027

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JO - Nature

JF - Nature

ER -

Dominant clones leverage developmental epigenomic states to drive ependymoma

Abstract

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