Hijacking a neurodevelopmental epigenomic program in metastatic dissemination of medulloblastoma

How dysregulation of neurodevelopment relates to medulloblastoma (MB), the most common pediatric brain tumor, remains elusive. Here, we uncovered a neurodevelopmental epigenomic program being hijacked to induce MB metastatic dissemination. Unsupervised analyses by integrating publicly available datasets with our newly generated data revealed that SMARCD3/BAF60C regulates DAB1-mediated Reelin signaling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements (CREs) at the DAB1 locus. We further identified that a core set of transcription factors, enhancer of zeste homolog 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the CREs at the SMARCD3 locus to form a chromatin hub for controlling SMARCD3 expression in the developing cerebellum and metastatic MB. Elevated SMARCD3 activates Reelin/DAB1-mediated Src kinase signaling, resulting in MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for MB patients.

[1]  G. Seelig,et al.  Spatial and cell-type transcriptional landscape of human cerebellar development , 2021, Nature Neuroscience.

[2]  H. Brem,et al.  Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma. , 2021, Journal of neurosurgery. Pediatrics.

[3]  Andrew J. Hill,et al.  A human cell atlas of fetal chromatin accessibility , 2020, Science.

[4]  Harrison W. Gabel,et al.  The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain , 2020, Nature Communications.

[5]  I. Pollack,et al.  Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma , 2020, Cancers.

[6]  Erwin G. Van Meir,et al.  Correction: EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway , 2019, Oncogene.

[7]  J. Buckner,et al.  A phase 1 and randomized, placebo‐controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872 , 2019, Cancer.

[8]  Volker Hovestadt,et al.  Resolving medulloblastoma cellular architecture by single-cell genomics , 2019, Nature.

[9]  Nada Jabado,et al.  Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs , 2018, Nature.

[10]  T. Fazzio,et al.  High‐Resolution Chromatin Profiling Using CUT&RUN , 2019, Current protocols in molecular biology.

[11]  D. Stearns,et al.  Inhibition of enhancer of zest homologue 2 is a potential therapeutic target for high‐MYC medulloblastoma , 2019, Neuropathology : official journal of the Japanese Society of Neuropathology.

[12]  D. Heck,et al.  Emerging connections between cerebellar development, behaviour and complex brain disorders , 2019, Nature Reviews Neuroscience.

[13]  Michael D. Taylor,et al.  Leptomeningeal dissemination: a sinister pattern of medulloblastoma growth. , 2019, Journal of neurosurgery. Pediatrics.

[14]  Björn Olsson,et al.  Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes , 2019, Bioinform..

[15]  N. Krogan,et al.  Dynamic BAF chromatin remodeling complex subunit inclusion promotes temporally distinct gene expression programs in cardiogenesis , 2019, Development.

[16]  J. Kong,et al.  Neuronal Migration During Development of the Cerebellum , 2018, Front. Cell. Neurosci..

[17]  Alexander S. Brown,et al.  Granule neuron precursor cell proliferation is regulated by NFIX and intersectin 1 during postnatal cerebellar development , 2018, Brain Structure and Function.

[18]  Jennifer L. Hadley,et al.  A Single-Cell Transcriptional Atlas of the Developing Murine Cerebellum , 2018, Current Biology.

[19]  Andrew C. Adey,et al.  Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data. , 2018, Molecular cell.

[20]  S. Raimondi,et al.  Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high‐grade and diffuse intrinsic pontine glioma , 2018, Pediatric blood & cancer.

[21]  Steven J. M. Jones,et al.  A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases , 2018, Cell.

[22]  T. Hughes,et al.  The Human Transcription Factors , 2018, Cell.

[23]  M. Roussel,et al.  Epigenetic Drivers in Pediatric Medulloblastoma , 2017, The Cerebellum.

[24]  J. Seidman,et al.  Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function , 2017, Biology Open.

[25]  Roland Eils,et al.  The whole-genome landscape of medulloblastoma subtypes , 2017, Nature.

[26]  A. Goldenberg,et al.  Intertumoral Heterogeneity within Medulloblastoma Subgroups. , 2017, Cancer cell.

[27]  A. Shilatifard,et al.  Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. , 2017, Cell reports.

[28]  Martin J. Aryee,et al.  OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma. , 2017, Cancer discovery.

[29]  Steven Henikoff,et al.  An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites , 2016, bioRxiv.

[30]  Ning Liu,et al.  Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth , 2016, Cell.

[31]  B. Coyle,et al.  In vitro models of medulloblastoma: Choosing the right tool for the job. , 2016, Journal of biotechnology.

[32]  Dmitri D. Pervouchine,et al.  Gene-specific patterns of expression variation across organs and species , 2016, Genome Biology.

[33]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[34]  Roland Eils,et al.  Active medulloblastoma enhancers reveal subgroup-specific cellular origins , 2016, Nature.

[35]  Shirley X. Liu,et al.  Integrative Analysis Reveals the Transcriptional Collaboration between EZH2 and E2F1 in the Regulation of Cancer-Related Gene Expression , 2015, Molecular Cancer Research.

[36]  Rezvan Ehsani,et al.  EpiFactors: a comprehensive database of human epigenetic factors and complexes , 2015, Database J. Biol. Databases Curation.

[37]  T. Butts,et al.  Development of the cerebellum: simple steps to make a ‘little brain’ , 2014, Development.

[38]  N. Wray,et al.  NFIB-Mediated Repression of the Epigenetic Factor Ezh2 Regulates Cortical Development , 2014, The Journal of Neuroscience.

[39]  David T. W. Jones,et al.  Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. , 2013, The Lancet. Oncology.

[40]  Howard Y. Chang,et al.  Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position , 2013, Nature Methods.

[41]  C. Perou,et al.  SWI/SNF Chromatin-Remodeling Factor Smarcd3/Baf60c Controls Epithelial-Mesenchymal Transition by Inducing Wnt5a Signaling , 2013, Molecular and Cellular Biology.

[42]  Roy V Sillitoe,et al.  Development of the cerebellum: from gene expression patterns to circuit maps , 2013, Wiley interdisciplinary reviews. Developmental biology.

[43]  M. Loda,et al.  EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent , 2012, Science.

[44]  Scott L. Pomeroy,et al.  Medulloblastomics: the end of the beginning , 2012, Nature Reviews Cancer.

[45]  P. Northcott,et al.  Targeting the enhancer of zeste homologue 2 in medulloblastoma , 2012, International journal of cancer.

[46]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[47]  M. Kool,et al.  EZH2-Regulated DAB2IP Is a Medulloblastoma Tumor Suppressor and a Positive Marker for Survival , 2012, Clinical Cancer Research.

[48]  R. McLendon,et al.  Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma , 2012, Journal of Neuro-Oncology.

[49]  Scott L. Pomeroy,et al.  Molecular subgroups of medulloblastoma: the current consensus , 2011, Acta Neuropathologica.

[50]  Qiang Yu,et al.  Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. , 2011, Molecular cell.

[51]  P. Adamson,et al.  Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  R. Beroukhim,et al.  Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure , 2011, Journal of Neuro-Oncology.

[53]  M. Ogawa,et al.  Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum , 2010, Neural Development.

[54]  Richard Hawkes,et al.  From clusters to stripes: The developmental origins of adult cerebellar compartmentation , 2008, The Cerebellum.

[55]  F. Rossi,et al.  Different Types of Cerebellar GABAergic Interneurons Originate from a Common Pool of Multipotent Progenitor Cells , 2006, The Journal of Neuroscience.

[56]  Jonathan A. Cooper,et al.  Absence of Fyn and Src Causes a Reeler-Like Phenotype , 2005, The Journal of Neuroscience.

[57]  Jeffrey L. Wrana,et al.  Baf60c is essential for function of BAF chromatin remodelling complexes in heart development , 2004, Nature.

[58]  F. Müller,et al.  The human brain at stages 18–20, including the choroid plexuses and the amygdaloid and septal nuclei , 2004, Anatomy and Embryology.

[59]  A. Goffinet,et al.  Reelin and brain development , 2003, Nature Reviews Neuroscience.

[60]  Joachim Herz,et al.  Reelin Activates Src Family Tyrosine Kinases in Neurons , 2003, Current Biology.

[61]  T. Curran,et al.  Identification of Reelin-induced Sites of Tyrosyl Phosphorylation on Disabled 1* , 2001, The Journal of Biological Chemistry.

[62]  T. Curran,et al.  Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. , 1998, Development.

[63]  T. Curran,et al.  A protein related to extracellular matrix proteins deleted in the mouse mutant reeler , 1995, Nature.

[64]  R L Sidman,et al.  Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans , 1970, The Journal of comparative neurology.

[65]  E. Housepian,et al.  An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. , 1969, Radiology.

[66]  J. Sneep,et al.  With a summary , 1945 .