scholarly journals Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

2018 ◽  
Author(s):  
James M. Stafford ◽  
Chul-Hwan Lee ◽  
Philipp Voigt ◽  
Nicolas Descostes ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Histone H3 ◽  
Dominant Negative ◽  
Pediatric Glioma ◽  
Multiple Modes ◽  
Paradoxical Effects ◽  
Diffuse Intrinsic Pontine Gliomas

ABSTRACTA methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

scholarly journals Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

2018 ◽  
Vol 4 (10) ◽  
pp. eaau5935 ◽  
Author(s):  
James M. Stafford ◽  
Chul-Hwan Lee ◽  
Philipp Voigt ◽  
Nicolas Descostes ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Histone H3 ◽  
Dominant Negative ◽  
Polycomb Repressive Complex ◽  
Chromatin Domains ◽  
Pediatric Glioma ◽  
Polycomb Repressive Complex 2 ◽  
Repressive Chromatin ◽  
Paradoxical Effects ◽  
Diffuse Intrinsic Pontine Gliomas

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2’s ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

scholarly journals Pericentromeric Heterochromatin Domains Are Maintained without Accumulation of HP1

2007 ◽  
Vol 18 (4) ◽  
pp. 1464-1471 ◽  
Author(s):  
Julio Mateos-Langerak ◽  
Maartje C. Brink ◽  
Martijn S. Luijsterburg ◽  
Ineke van der Kraan ◽  
Roel van Driel ◽  
...  
Keyword(s):  
Histone H3 ◽  
Dominant Negative ◽  
Pericentromeric Heterochromatin ◽  
Heterochromatin Protein 1 ◽  
Dapi Staining ◽  
Heterochromatin Protein ◽  
3T3 Fibroblasts ◽  
Heterochromatin Structure ◽  
Hp1 Proteins

The heterochromatin protein 1 (HP1) family is thought to be an important structural component of heterochromatin. HP1 proteins bind via their chromodomain to nucleosomes methylated at lysine 9 of histone H3 (H3K9me). To investigate the role of HP1 in maintaining heterochromatin structure, we used a dominant negative approach by expressing truncated HP1α or HP1β proteins lacking a functional chromodomain. Expression of these truncated HP1 proteins individually or in combination resulted in a strong reduction of the accumulation of HP1α, HP1β, and HP1γ in pericentromeric heterochromatin domains in mouse 3T3 fibroblasts. The expression levels of HP1 did not change. The apparent displacement of HP1α, HP1β, and HP1γ from pericentromeric heterochromatin did not result in visible changes in the structure of pericentromeric heterochromatin domains, as visualized by DAPI staining and immunofluorescent labeling of H3K9me. Our results show that the accumulation of HP1α, HP1β, and HP1γ at pericentromeric heterochromatin domains is not required to maintain DAPI-stained pericentromeric heterochromatin domains and the methylated state of histone H3 at lysine 9 in such heterochromatin domains.

scholarly journals PDTM-39. HISTONE H3 MUTATION EFFECTS ON CHROMATIN STRUCTURE AND REGULATION OF GENE TRANSCRIPTION IN PEDIATRIC GLIOMA

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi212-vi212
Author(s):  
Amanda Saratsis ◽  
Tina Huang ◽  
Andrea Piunti ◽  
Patrick A. Ozark ◽  
Elizabeth Bartom ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Chromatin Structure ◽  
Histone H3 ◽  
Pediatric Glioma

Pontine tumor in a neonate: case report and analysis of the current literature

2019 ◽  
Vol 23 (5) ◽  
pp. 606-612
Author(s):  
Constanze Buus-Gehrig ◽  
Thomas Lehrnbecher ◽  
Luciana Porto ◽  
Martina Becker ◽  
Thomas Freiman ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Posterior Fossa ◽  
Pilocytic Astrocytoma ◽  
Pediatric Patients ◽  
Intensive Therapy ◽  
Neurological Development ◽  
Pediatric Glioma ◽  
The Central Nervous System ◽  
Brainstem Tumors ◽  
Diffuse Intrinsic Pontine Gliomas

Tumors of the central nervous system represent the largest group of solid tumors found in pediatric patients. Pilocytic astrocytoma is the most common pediatric glioma, mostly located in the posterior fossa. The majority of brainstem tumors, however, are classified as highly aggressive diffuse intrinsic pontine gliomas (DIPGs) and their prognosis is dismal.The authors report on the case of a neonate in whom MRI and neuropathological assessment were used to diagnose DIPG. Before initiation of the planned chemotherapy, the tumor regressed spontaneously, and the newborn exhibited a normal neurological development. Meanwhile, Illumina Human Methylation450 BeadChip analysis reclassified the tumor as pilocytic astrocytoma of the posterior fossa.In conclusion, the authors advocate not initiating immediate intensive therapy in newborns with brain tumors, even with classical appearance of a DIPG; rather, they would like to encourage a biopsy to define the best individual therapeutic approach and avoid ineffective chemotherapy.

scholarly journals Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 660 ◽  
Author(s):  
Brandon R. Lowe ◽  
Lily A. Maxham ◽  
Joshua J. Hamey ◽  
Marc R. Wilkins ◽  
Janet F. Partridge
Keyword(s):  
Recent Progress ◽  
Histone H3 ◽  
High Grade Glioma ◽  
Central Importance ◽  
Giant Cell Tumors ◽  
Pediatric Glioma ◽  
Genes Encoding ◽  
Tumors Of Bone ◽  
Pediatric High Grade Glioma

In this review, we describe the attributes of histone H3 mutants identified in cancer. H3 mutants were first identified in genes encoding H3.3, in pediatric high-grade glioma, and subsequently in chondrosarcomas and giant cell tumors of bone (GCTB) in adolescents. The most heavily studied are the lysine to methionine mutants K27M and K36M, which perturb the target site for specific lysine methyltransferases and dominantly perturb methylation of corresponding lysines in other histone H3 proteins. We discuss recent progress in defining the consequences of these mutations on chromatin, including a newly emerging view of the central importance of the disruption of H3K36 modification in many distinct K to M histone mutant cancers. We also review new work exploring the role of H3.3 G34 mutants identified in pediatric glioma and GCTB. G34 is not itself post-translationally modified, but G34 mutation impinges on the modification of H3K36. Here, we ask if G34R mutation generates a new site for methylation on the histone tail. Finally, we consider evidence indicating that histone mutations might be more widespread in cancer than previously thought, and if the perceived bias towards mutation of H3.3 is real or reflects the biology of tumors in which the histone mutants were first identified.

scholarly journals PDTB-14. INVESTIGATING HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS USING PARAFFIN-EMBEDDED PEDIATRIC GLIOMA TISSUE SAMPLES

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi152-vi153
Author(s):  
Amanda Saratsis ◽  
Tina Huang ◽  
Andrea Piunti ◽  
Rintaro Hashizume ◽  
Elizabeth Bartom ◽  
...  
Keyword(s):  
Histone H3 ◽  
Glioma Tissue ◽  
Tissue Samples ◽  
Post Translational Modifications ◽  
Pediatric Glioma

scholarly journals Dominant-Negative Histone H3 Lysine 27 Mutant Derepresses Silenced Tumor Suppressor Genes and Reverses the Drug-Resistant Phenotype in Cancer Cells

2006 ◽  
Vol 66 (11) ◽  
pp. 5582-5591 ◽  
Author(s):  
Phillip H. Abbosh ◽  
John S. Montgomery ◽  
Jason A. Starkey ◽  
Milos Novotny ◽  
Eleanor G. Zuhowski ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Histone H3 ◽  
Dominant Negative ◽  
Drug Resistant ◽  
Suppressor Genes ◽  
Resistant Phenotype ◽  
Drug Resistant Phenotype

scholarly journals DIPG-58. HISTONE H3 WILD-TYPE DIPG/DMG OVEREXPRESSING EZHIP EXTEND THE SPECTRUM OF DIFFUSE MIDLINE GLIOMAS WITH PRC2 INHIBITION BEYOND H3-K27M MUTATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii298-iii298
Author(s):  
David Castel ◽  
Thomas Kergrohen ◽  
Arnault Tauziède-Espariat ◽  
Alan Mackay ◽  
Samia Ghermaoui ◽  
...  
Keyword(s):  
Histone H3 ◽  
Registry Study ◽  
Wild Type ◽  
H3k27 Trimethylation ◽  
K27m Mutation ◽  
Repressor Complex ◽  
Diffuse Gliomas ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
H3 K27m Mutations ◽  
Made In

Abstract Diffuse midline gliomas (DMG) H3 K27M-mutant were introduced in the 2016 WHO Classification unifying diffuse intrinsic pontine gliomas (DIPG) and gliomas from the thalamus and spinal cord harboring a histone H3-K27M mutation leading to Polycomb Repressor Complex 2 (PRC2) inhibition. However, few cases of DMG tumors presenting a H3K27 trimethylation loss, but lacking an H3-K27M mutation were reported. To address this question, we combined a retrospective cohort of 10 patients biopsied for a DIPG at the Necker Hospital or included in the BIOMEDE trial (NCT02233049) and extended our analysis to H3-wildtype (WT) diffuse gliomas from other midline locations presenting either H3K27 trimethylation loss or ACVR1 mutation from Necker, ICR, the HERBY trial, the INFORM registry study and the St. Jude PCGP representing 9 additional cases. Genomic profiling identified alterations frequently found in DMG, but none could explain the observed loss of H3K27 trimethylation. Similar observations were previously made in the PF-A subgroup of ependymoma, where the H3K27me3 loss resulted from EZHIP/CXorf67 overexpression rather than H3-K27M mutations. We thus analyzed EZHIP expression and observed its overexpression in all but one H3-WT DMGs compared to H3-K27M mutated tumors (EZHIP negative). Strikingly, based on their DNA methylation profiles, all H3-WT DMG samples analyzed clustered close to H3-K27M DIPG, rather than EZHIP overexpressing PF-A ependymomas. To conclude, we described a new subgroup of DMG lacking H3-K27M mutation, defined by H3K27 trimethylation loss and EZHIP overexpression that can be detected by IHC. We propose that these EZHIP/H3-WT DMGs extend the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation.

EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death

2004 ◽  
Vol 287 (5) ◽  
pp. F1049-F1058 ◽  
Author(s):  
Jing Dong ◽  
Sampath Ramachandiran ◽  
Kulbhushan Tikoo ◽  
Zhe Jia ◽  
Serrine S. Lau ◽  
...  
Keyword(s):  
Cell Death ◽  
P38 Mapk ◽  
Egf Receptor ◽  
Histone H3 ◽  
Dominant Negative ◽  
Mapk Activation ◽  
Transfected Cells ◽  
H3 Phosphorylation ◽  
Hsp27 Phosphorylation ◽  
Histone H3 Phosphorylation

2,3,5-Tris-(glutathion- S-yl)hydroquinone (TGHQ), a reactive metabolite of the nephrotoxicant hydroquinone, induces the ROS-dependent activation of MAPKs, followed by histone H3 phosphorylation and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). Cell death and histone H3 phosphorylation are attenuated by pharmacological inhibition of p38 MAPK or ERK1/2 pathways. Because TGHQ, but not epidermal growth factor (EGF), induces histone H3 phosphorylation and cell death in LLC-PK1 cells, we hypothesized that there are differences in the mechanisms by which TGHQ and EGF induce activation of the EGF receptor (EGFR). We therefore compared the relative ability of TGHQ, H2O2, and EGF to activate EGFR and MAPKs and found that p38 MAPK activation is EGFR independent, whereas ERK1/2 activation occurs mainly through EGFR activation. TGHQ, H2O2, and EGF induce different EGFR tyrosine phosphorylation profiles that likely influence the subsequent differential kinetics of MAPK activation. We next transfected LLC-PK1 cells with a dominant negative p38 MAPK-expressing plasmid (pcDNA3-DNp38). TGHQ failed to induce phosphorylation of p38 MAPK and its substrate, MK-2, in pcDNA3-DNp38-transfected cells, indicating loss of function of p38 MAPK. In untransfected, pcDNA3 or pcDNA3-p38 (native)-transfected LLC-PK1 cells, Hsp27 was intensively phosphorylated after TGHQ treatment, whereas in pcDNA3-DNp38-transfected cells, TGHQ failed to induce Hsp27 phosphorylation. Thus EGFR-independent p38 MAPK and EGFR-dependent ERK1/2 activation by TGHQ lead to the activation of two downstream signaling factors, i.e., histone H3 and Hsp27 phosphorylation, which have in common the potential ability to remodel chromatin.

scholarly journals PDTB-13. DETECTION OF HISTONE H3 MUTATIONS IN PEDIATRIC GLIOMA VIA TUMOR DNA DERIVED FROM CEREBROSPINAL FLUID

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi152-vi152
Author(s):  
Amanda Saratsis ◽  
Tina Huang ◽  
Andrea Piunti ◽  
Rishi Lulla ◽  
Tadanori Tomita ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Histone H3 ◽  
Pediatric Glioma ◽  
Tumor Dna
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