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@ARTICLE{Pun:267545,
      author       = {M. Pun and D. Pratt and P. R. Nano and P. K. Joshi$^*$ and
                      L. Jiang and B. Englinger and A. Rao and M. Cieslik and A.
                      M. Chinnaiyan and K. Aldape and S. Pfister$^*$ and M. G.
                      Filbin and A. Bhaduri and S. Venneti},
      title        = {{C}ommon molecular features of {H}3{K}27{M} {DMG}s and
                      {PFA} ependymomas map to hindbrain developmental pathways.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {11},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2023-00323},
      pages        = {25},
      year         = {2023},
      abstract     = {Globally decreased histone 3, lysine 27 tri-methylation
                      (H3K27me3) is a hallmark of H3K27-altered diffuse midline
                      gliomas (DMGs) and group-A posterior fossa ependymomas
                      (PFAs). H3K27-altered DMGs are largely characterized by
                      lysine-to-methionine mutations in histone 3 at position 27
                      (H3K27M). Most PFAs overexpress EZH inhibitory protein
                      (EZHIP), which possesses a region of similarity to the
                      mutant H3K27M. Both H3K27M and EZHIP inhibit the function of
                      the polycomb repressive complex 2 (PRC2) responsible for
                      H3K27me3 deposition. These tumors often arise in neighboring
                      regions of the brainstem and posterior fossa. In rare cases
                      PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP.
                      These findings together raise the possibility that certain
                      cell populations in the developing hindbrain/posterior fossa
                      are especially sensitive to modulation of H3K27me3 states.
                      We identified shared molecular features by comparing
                      genomic, bulk transcriptomic, chromatin-based profiles, and
                      single-cell RNA-sequencing (scRNA-seq) data from the two
                      tumor classes. Our approach demonstrated that 1q gain, a key
                      biomarker in PFAs, is prognostic in H3.1K27M, but not
                      H3.3K27M gliomas. Conversely, Activin A Receptor Type 1
                      (ACVR1), which is associated with mutations in H3.1K27M
                      gliomas, is overexpressed in a subset of PFAs with poor
                      outcome. Despite diffuse H3K27me3 reduction, previous work
                      shows that both tumors maintain genomic H3K27me3 deposition
                      at select sites. We demonstrate heterogeneity in shared
                      patterns of residual H3K27me3 for both tumors that largely
                      segregated with inferred anatomic tumor origins and
                      progenitor populations of tumor cells. In contrast, analysis
                      of genes linked to H3K27 acetylation (H3K27ac)-marked
                      enhancers showed higher expression in astrocytic-like tumor
                      cells. Finally, common H3K27me3-marked genes mapped closely
                      to expression patterns in the human developing hindbrain.
                      Overall, our data demonstrate developmentally relevant
                      molecular similarities between PFAs and H3K27M DMGs and
                      support the overall hypothesis that deregulated mechanisms
                      of hindbrain development are central to the biology of both
                      tumors.},
      keywords     = {Humans / Histones: genetics / Histones: metabolism /
                      Lysine: genetics / Ependymoma: pathology / Glioma: genetics
                      / Glioma: pathology / Rhombencephalon: pathology /
                      Fluorocarbons / Mutation: genetics / Brain Neoplasms:
                      genetics / Brain Neoplasms: pathology / Brain development
                      (Other) / Cancer (Other) / Chromatin biology (Other) /
                      Neuro-oncology (Other) / Onco-histones (Other) / Pediatric
                      tumors (Other) / Histones (NLM Chemicals) / Lysine (NLM
                      Chemicals) / Fluorocarbons (NLM Chemicals)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36759899},
      pmc          = {pmc:PMC9912509},
      doi          = {10.1186/s40478-023-01514-z},
      url          = {https://inrepo02.dkfz.de/record/267545},
}