Ran Tao, Serap Erkek-Ozhan, Beisi Xu, Yurika Matsui, Priya Mittal, Kyle S Smith, Yiran Li, David Filipovic, Ruijie Xu, Qingsong Gao, Emily Darrow, Rahul Kumar, Nadhir Djekidel, Richa Bajpai, Jennifer Hadley, Melissa Batts, Sara A Lewis, Taha Soliman, Colleen Reilly, Natarajan V Bhanu, Leena Paul, Hong Lin, Brian Gudenas, Kim Lowe, Marc Zapatka, Laura Sieber, David T W Jones, Marcel Kool, Sebastian M Waszak, Volker Hovestadt, Ivo Buchhalter, Marina Ryzhova, Andrey Korshunov, Peter Lichter, Lukas Chavez, Lena M Kutscher, Benjamin A Garcia, Shondra M Pruett-Miller, Xin Zhou, Brent A Orr, Giles W Robinson, Gang Wu, Jan O Korbel, Jamy C Peng, Stefan M Pfister, Paul A Northcott
Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across medulloblastoma subgroups by multi-modal integration of histone modifications with mutational, DNA methylation and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Group 3/4 medulloblastoma. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of medulloblastoma models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.