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1.
Cell ; 187(18): 4926-4945.e22, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38986619

RESUMO

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.


Assuntos
Ependimoma , Ependimoma/genética , Humanos , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/patologia , Genoma Humano , Lactente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Masculino , Feminino
2.
Cell ; 183(6): 1617-1633.e22, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33259802

RESUMO

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Transcriptoma/genética
3.
Hum Mol Genet ; 29(5): 785-802, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-31943018

RESUMO

Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.


Assuntos
Astrócitos/patologia , Adesão Celular , Síndrome de Down/patologia , Regulação da Expressão Gênica , Genoma Humano , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Neurais/patologia , Astrócitos/metabolismo , Diferenciação Celular , Movimento Celular , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Transcriptoma
4.
Dev Neurosci ; 43(6): 321-334, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34348288

RESUMO

Angiopoietin1 (Angpt1) is a secreted protein that activates the endothelial Tie2 receptor. Angpt1 plays a critical role in cardiac development and vascular remodeling in response to disease or injury and shows cell type-restricted expression in the lung, eye, and hematopoietic system. However, the expression of Angpt1 in the developing and adult brain is not known. Here, we employ Angpt1-GFP knock-in reporter mice and a systematic analysis of multiple single-cell RNA sequencing datasets to map the expression of Angpt1 during brain development and adulthood. In the developing brain, Angpt1 displays specific spatiotemporal patterns, with strong expression in cerebellar GABA interneuron progenitors and, to a lower level, in glial progenitor and astrocyte lineages. In the adult brain, on the other hand, we show that neurons are the main source of Angpt1 in the cerebrum, while in the cerebellum, expression is mostly restricted to astrocytes. Together, our data provide clarity on the cell types that express Angpt1 in the developing and adult brain and can be utilized to guide future studies, examining Angpt1 function in brain development, homeostasis, and pathological conditions.


Assuntos
Angiopoietina-1 , Receptor TIE-2 , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Camundongos , Receptor TIE-2/genética , Receptor TIE-2/metabolismo
5.
Bioinformatics ; 34(13): 2286-2288, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29438498

RESUMO

Summary: Chromatin state plays a major role in controlling gene expression, and comparative analysis of ChIP-seq data is key to understanding epigenetic regulation. We present chromswitch, an R/Bioconductor package to integrate epigenomic data in a defined window of interest to detect an overall switch in chromatin state. Chromswitch accurately classifies a benchmarking dataset, and when applied genome-wide, the tool successfully detects chromatin changes that result in brain-specific expression. Availability and implementation: Chromswitch is implemented as an R package available from Bioconductor at https://bioconductor.org/packages/chromswitch. All data and code for reproducing the analysis presented in this paper are available at https://doi.org/10.5281/zenodo.1101260. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Cromatina , Epigênese Genética , Epigenômica , Genoma , Software
6.
Nat Commun ; 15(1): 7769, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237515

RESUMO

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.


Assuntos
Neoplasias Encefálicas , Glioma , Histonas , Mutação , Células Mieloides , Microambiente Tumoral , Animais , Glioma/genética , Glioma/imunologia , Glioma/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Células Mieloides/metabolismo , Células Mieloides/imunologia , Histonas/metabolismo , Histonas/genética , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Humanos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Regulação Neoplásica da Expressão Gênica , Análise de Célula Única
7.
Nat Genet ; 54(12): 1865-1880, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36471070

RESUMO

Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.


Assuntos
Cromatina , Epigenômica , Linhagem da Célula/genética , Encéfalo
8.
Contrast Media Mol Imaging ; 2021: 1250360, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803544

RESUMO

Purpose: The majority of X-ray contrast agents (XCA) are made with iodine, but iodine-based XCA (I-XCA) exhibit low contrast in high kVp X-rays due to iodine's low atomic number (Z = 53) and K-edge (33.1 keV). While rhenium is a transition metal with a high atomic number (Z = 75) and K-edge (71.7 keV), the utilization of rhenium-based XCA (Re-XCA) in X-ray imaging techniques has not been studied in depth. Our study had two objectives: (1) to compare both the image quality and the absorbed dose of I- and Re-XCA and (2) to prepare and image a rhenium-doped scaffold. Procedures. I- and Re-XCA were prepared and imaged from 50 to 120 kVp by Micro-computed tomography (µCT) and digital radiography and from 120 to 220 kVp by planar X-ray imaging. The scans were repeated using 0.1 to 1.6 mm thick copper filters to harden the X-ray beam. A rhenium-doped scaffold was prepared via electrospinning, used to coat catheters, and imaged at 90 kVp by µCT. Results: I-XCA have a greater contrast-to-noise ratio (CNR) at 50 and 80 kVp, but Re-XCA have a greater CNR at >120 kVp. The difference in CNR is increased as the thickness of the copper filters is increased. For instance, the percent CNR improvement of rhenium over iodine is 14.2% with a 0.6 mm thick copper filter, but it is 59.1% with a 1.6 mm thick copper filter, as shown at 120 kVp by µCT. Upon coating them with a rhenium-doped scaffold, the catheters became radiopaque. Conclusions: Using Monte Carlo simulations, we showed that it is possible to reduce the absorbed dose of high kVp X-rays while allowing the acquisition of high-quality images. Furthermore, radiopaque catheters have the potential of enhancing the contrast during catheterizations and helping physicians to place catheters inside patients more rapidly and precisely.


Assuntos
Iodo , Rênio , Meios de Contraste , Humanos , Imagens de Fantasmas , Microtomografia por Raio-X , Raios X
9.
Sci Transl Med ; 13(615): eabf7860, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34644147

RESUMO

High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier­penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.


Assuntos
Neoplasias Encefálicas , Glioma , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Epigênese Genética , Glioma/genética , Glicina , Histonas/metabolismo , Humanos , Camundongos
10.
Cancer Discov ; 11(9): 2200-2215, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33741710

RESUMO

More than 60% of supratentorial ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. SIGNIFICANCE: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA-RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113.


Assuntos
Proteínas de Ligação a DNA/genética , Ependimoma/genética , Neoplasias Supratentoriais/genética , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética , Animais , Modelos Animais de Doenças , Ependimoma/patologia , Camundongos , Neoplasias Supratentoriais/patologia
11.
Sci Rep ; 10(1): 581, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953485

RESUMO

While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of latency in the evolutionary path of metastatic CRC and may have implications for future treatment options.


Assuntos
Neoplasias Colorretais/genética , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Frequência do Gene , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Fatores de Tempo , Sequenciamento do Exoma
12.
Nat Genet ; 51(12): 1702-1713, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768071

RESUMO

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Lactente , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única
13.
Nat Commun ; 9(1): 4001, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275490

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Reguladores/genética , Variação Genética , Genoma Humano/genética , Linfoma Difuso de Grandes Células B/genética , Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Exoma/genética , Estudo de Associação Genômica Ampla , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Proteínas I-kappa B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Mutação , Proteínas Nucleares/genética , Receptores de IgG/genética , Análise de Sequência de DNA , Transcriptoma
14.
Gigascience ; 6(5): 1-13, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28327945

RESUMO

The field of cancer genomics has demonstrated the power of massively parallel sequencing techniques to inform on the genes and specific alterations that drive tumor onset and progression. Although large comprehensive sequence data sets continue to be made increasingly available, data analysis remains an ongoing challenge, particularly for laboratories lacking dedicated resources and bioinformatics expertise. To address this, we have produced a collection of Galaxy tools that represent many popular algorithms for detecting somatic genetic alterations from cancer genome and exome data. We developed new methods for parallelization of these tools within Galaxy to accelerate runtime and have demonstrated their usability and summarized their runtimes on multiple cloud service providers. Some tools represent extensions or refinement of existing toolkits to yield visualizations suited to cohort-wide cancer genomic analysis. For example, we present Oncocircos and Oncoprintplus, which generate data-rich summaries of exome-derived somatic mutation. Workflows that integrate these to achieve data integration and visualizations are demonstrated on a cohort of 96 diffuse large B-cell lymphomas and enabled the discovery of multiple candidate lymphoma-related genes. Our toolkit is available from our GitHub repository as Galaxy tool and dependency definitions and has been deployed using virtualization on multiple platforms including Docker.


Assuntos
Genômica , Linfoma Difuso de Grandes Células B/genética , Software , Algoritmos , Humanos , Internet , Mutação , Fluxo de Trabalho
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