RESUMEN
RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.
Asunto(s)
Neoplasias Óseas , Exones , Tumor Óseo de Células Gigantes , Humanos , Tumor Óseo de Células Gigantes/genética , Tumor Óseo de Células Gigantes/metabolismo , Tumor Óseo de Células Gigantes/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Histonas/metabolismo , Histonas/genética , Células HeLa , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/genética , Empalme del ARN , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Empalme AlternativoRESUMEN
The role of the muscle circadian clock in regulating oxidative metabolism exerts a significant influence on whole-body energy metabolism; however, research on the connection between the muscle circadian clock and obesity is limited. Moreover, there is a lack of studies demonstrating the regulatory effects of dietary butyrate on muscle circadian clock and the resulting antiobesity effects. This study aimed to investigate the impacts of dietary butyrate on metabolic and microbiome alterations and muscle circadian clock in a diet-induced obesity model. Male Sprague-Dawley rats were fed a high-fat diet with or without butyrate. Gut microbiota and serum metabolome were analyzed, and molecular changes were examined using tissues and a cell line. Further correlation analysis was performed on butyrate-induced results. Butyrate supplementation reduced weight gain, even with increased food intake. Gut microbiome analysis revealed an increased abundance of Firmicutes in butyrate group. Serum metabolite profile in butyrate group exhibited reduced amino acid and increased fatty acid content. Muscle circadian clock genes were upregulated, resulting in increased transcription of fatty acid oxidation-related genes. In myoblast cells, butyrate also enhanced pan-histone acetylation via histone deacetylase inhibition, particularly modulating acetylation at the promoter of circadian clock genes. Correlation analysis revealed potential links between Firmicutes phylum, including certain genera within it, and butyrate-induced molecular changes in muscle as well as phenotypic alterations. The butyrate-driven effects on diet-induced obesity were associated with alterations in gut microbiota and a muscle-specific increase in histone acetylation, leading to the transcriptional activation of circadian clock genes and their controlled genes.
Asunto(s)
Relojes Circadianos , Microbioma Gastrointestinal , Animales , Ratas , Masculino , Relojes Circadianos/genética , Butiratos/farmacología , Butiratos/metabolismo , Histonas/metabolismo , Epigénesis Genética , Ratas Sprague-Dawley , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismoRESUMEN
Cordyceps militaris is rich in adenosine derivatives, including 3'-deoxyadenosine, also known as cordycepin. It has been reported for antitumor effects, but its underlying molecular mechanism has yet to be elucidated. We investigated how adenosine derivatives exerted antitumor effects against ovarian cancer using human ovarian cancer cells and a xenograft mouse model. Treatment with adenosine derivatives effectively resulted in cell death of ovarian cancer cells through AMPK activation and subsequently mTOR-mediated autophagic induction. Intriguingly, the effect required membrane transport of adenosine derivatives via ENT1, rather than ADORA-mediated cellular signaling. Our data suggest that adenosine derivatives may be an effective therapeutic intervention in ovarian cancer through induction of ENT1-AMPK-mTOR-mediated autophagic cell death.
Asunto(s)
Adenosina , Muerte Celular Autofágica , Cordyceps , Neoplasias Ováricas , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Animales , Muerte Celular Autofágica/efectos de los fármacos , Carcinoma Epitelial de Ovario , Cordyceps/química , Desoxiadenosinas/farmacología , Tranportador Equilibrativo 1 de Nucleósido/efectos de los fármacos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Femenino , Humanos , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.
Asunto(s)
Neoplasias Óseas/genética , Tumor Óseo de Células Gigantes/genética , Histonas/genética , Osteogénesis , Neoplasias Óseas/metabolismo , Neoplasias Óseas/fisiopatología , Metilación de ADN , Epigénesis Genética , Epigenómica , Tumor Óseo de Células Gigantes/metabolismo , Tumor Óseo de Células Gigantes/fisiopatología , Histonas/metabolismo , Humanos , Mutación MissenseRESUMEN
The last decade's progress unraveling the mutational landscape of all age groups of cancer has uncovered mutations in histones as vital contributors of tumorigenesis. Here we review three new aspects of oncogenic histones: first, the identification of additional histone mutations potentially contributing to cancer formation; second, tumors expressing histone mutations to study the crosstalk of post-translational modifications, and; third, development of sophisticated biological model systems to reproduce tumorigenesis. At the outset, we recapitulate the firstly discovered histone mutations in pediatric and adolescent tumors of the brain and bone, which still remain the most pronounced histone alterations in cancer. We branch out to discuss the ramifications of histone mutations, including novel ones, that stem from altered protein-protein interactions of cognate histone modifiers as well as the stability of the nucleosome. We close by discussing animal models of oncogenic histones that reproduce tumor formation molecularly and morphologically and the prospect of utilizing them for drug testing, leading to efficient treatment and cure of deadly cancers with histone mutations.
Asunto(s)
Modelos Animales de Enfermedad , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Mutación , Neoplasias/genética , Nucleosomas/genética , Animales , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , RatonesRESUMEN
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes mono- and di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Muerte Celular , Colesterol/biosíntesis , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células Tumorales CultivadasRESUMEN
Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.
Asunto(s)
Neoplasias Óseas/genética , Perfilación de la Expresión Génica , Tumor Óseo de Células Gigantes/genética , Histonas/genética , Mapas de Interacción de Proteínas , Humanos , MutaciónRESUMEN
The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.
RESUMEN
While transcription as regulated by histones and their post-translational modifications has been well described, the function of histone variants in this process remains poorly characterized. Potentially important insight into this process pertain to the frequently occurring mutations of H3.3, leading to G34 substitutions in childhood glioblastoma and giant cell tumor of the bone (GCTB). In this study, we have established primary cell lines from GCTB patients and used them to uncover the influence of H3.3 G34W substitutions on cellular growth behavior, gene expression, and chromatin compaction. Primary cell lines with H3.3 G34W showed increased colony formation, infiltration and proliferation, known hallmarks of tumor development. Isogenic cell lines with H3.3 G34W recapitulated the increased proliferation observed in primary cells. Transcriptomic analysis of primary cells and tumor biopsies revealed slightly more downregulated gene expression, perhaps by increased chromatin compaction. We identified components related to splicing, most prominently hnRNPs, by immunoprecipitation and mass spectrometry that specifically interact with H3.3 G34W in the isogenic cell lines. RNA-sequencing analysis and hybridization-based validations further enforced splicing aberrations. Our data uncover a role for H3.3 in RNA processing and chromatin modulation that is blocked by the G34W substitution, potentially driving the tumorigenic process in GCTB.
Asunto(s)
Sustitución de Aminoácidos , Neoplasias Óseas/genética , Cromatina/genética , Tumor Óseo de Células Gigantes/genética , Histonas/genética , Mutación , Procesamiento Postranscripcional del ARN , Neoplasias Óseas/diagnóstico , Proteínas Portadoras , Línea Celular Tumoral , Cromatina/metabolismo , Cromatografía Liquida , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Tumor Óseo de Células Gigantes/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Histonas/metabolismo , Humanos , Masculino , Modelos Biológicos , Unión Proteica , Mapeo de Interacción de Proteínas , Espectrometría de Masas en Tándem , TranscriptomaRESUMEN
This corrects the article DOI: 10.1038/ng.3889.
RESUMEN
BACKGROUND: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells. METHODS: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling. RESULTS: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers. CONCLUSIONS: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.
Asunto(s)
Proteínas Portadoras/genética , Neoplasias del Colon/genética , Metilación de ADN/genética , Transición Epitelial-Mesenquimal/genética , Proteínas Nucleares/genética , Proteínas Portadoras/antagonistas & inhibidores , Línea Celular Tumoral , Senescencia Celular/genética , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Proteínas Nucleares/antagonistas & inhibidores , Transcriptoma/genéticaRESUMEN
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Muerte Celular/genética , Código de Histonas , Inhibidores de Histona Desacetilasas/farmacología , Secuencias Repetidas Terminales/genética , Sitio de Iniciación de la Transcripción/efectos de los fármacos , Empalme Alternativo/genética , Animales , Bencimidazoles/farmacología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/fisiología , Metilación de ADN , Proteínas Quinasas Asociadas a Muerte Celular/antagonistas & inhibidores , Represión Epigenética , Exones/genética , Femenino , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Ácidos Hidroxámicos/farmacología , Intrones/genética , Ratones , Ratones Desnudos , Interferencia de ARN , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , VorinostatRESUMEN
BACKGROUND: The Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress. Its underlying mechanisms, however, remain unclear. In latest decades, emerging evidence has suggested that epigenetic mechanisms play a key role in gene regulation in response to the cellular stress. We investigated whether epigenetic modulation was involved in neuronal cell death by the neurotoxicant, 1-Methyl-4-phenylpyridinium (MPP(+)), and the neuroprotective effect of PLE. METHODS: Differentiated SH-SY5Y, which is a well-established dopaminergic cell line model, was treated with 0 ~ 200 µg/ml PLE for 4 h prior to MPP(+) treatment. The effect of PLE on cell viability was determined by MTT assays. Gene expression levels of oxidative stress responsive genes, such as Heme oxygenase 1 (HMOX1), and histone modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs) were measured by quantitative RT PCR. In order to investigate the changes in epigenetic modifications, the acetylated lysine 9 (H3K9ac) and lysine 27 (H3K27ac) of Histone H3 were measured by western blot using histones extracted from the cells. RESULTS: MPP(+)-induced cell death in SH-SY5Y cells was significantly reduced by PLE pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of PLE. It was accompanied by induced expression of HMOX1. MPP(+) treatment increased the expression of HATs and consistently increased H3K9ac and H3K27ac of Histone H3. PLE pretreatment impeded the changes in H3K9ac and H3K27ac, coincided with increased expression of HDAC5 without changes in HAT expression. CONCLUSIONS: The results suggested that MPP(+)-induced cell death in the dopaminergic SH-SY5Y cells was related with transcriptional induction of HATs and increased histone H3 acetylation and that PLE might prevent the cells from MPP(+)-induced cell death via tempering histone H3 acetylation.
Asunto(s)
Apoptosis/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Paeonia/química , Extractos Vegetales/farmacología , Acetilación , Línea Celular Tumoral , Hemo-Oxigenasa 1/metabolismo , Histonas/metabolismo , Humanos , Fármacos Neuroprotectores/química , Extractos Vegetales/químicaRESUMEN
The histone-modifying PRC2 complex has an ambiguous role in cancer, bearing both oncogenic and tumor-suppressive features depending on cell type. Studies of malignant peripheral nerve sheath tumors (MPNSTs) have now identified loss-of-function mutations altering PRC2 subunits, leading to the amplification of Ras-driven transcription and conferring vulnerability to BRD4 inhibitors.
Asunto(s)
Modelos Biológicos , Neurilemoma/genética , Complejo Represivo Polycomb 2/deficiencia , Transducción de Señal/fisiología , Proteínas ras/metabolismo , Proteínas de Ciclo Celular , Genes de Neurofibromatosis 1/fisiología , Humanos , Proteínas de Neoplasias , Proteínas Nucleares/antagonistas & inhibidores , Complejo Represivo Polycomb 2/genética , Transducción de Señal/genética , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética/fisiologíaRESUMEN
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
Asunto(s)
5-Metilcitosina/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular/metabolismo , Citosina/análogos & derivados , Metilación de ADN/fisiología , Neoplasias/genética , Proteínas Nucleares/metabolismo , ARN Largo no Codificante/fisiología , Timina ADN Glicosilasa/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Islas de CpG/fisiología , Citosina/metabolismo , Metilación de ADN/genética , Reparación del ADN/genética , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Células HEK293 , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/fisiología , ARN Largo no Codificante/genéticaRESUMEN
Comprehensive sequencing of benign and malignant tumors has recently uncovered new driver mutations in childhood tumors. A new report now describes frequent histone H3.3 alterations in chondroblastoma and giant cell tumor of bone, emphasizing the importance of this histone variant in pediatric cancers.
Asunto(s)
Neoplasias Óseas/genética , Condroblastoma/genética , Tumor Óseo de Células Gigantes/genética , Histonas/genética , HumanosRESUMEN
Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in â¼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias del Tronco Encefálico/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Histonas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias del Tronco Encefálico/metabolismo , Línea Celular Tumoral , Niño , Epigénesis Genética , Genes Dominantes , Glioblastoma/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Humanos , Metilación , Datos de Secuencia Molecular , Mutación Missense , Proteínas de Neoplasias , Complejo Represivo Polycomb 2/metabolismo , Unión Proteica , Procesamiento Proteico-Postraduccional , Factores de Transcripción , Transcripción GenéticaRESUMEN
Malignancies are characterized by extensive global reprogramming of epigenetic patterns, including gains or losses in DNA methylation and changes to histone marks. Furthermore, high-resolution genome-sequencing efforts have discovered a wealth of mutations in genes encoding epigenetic regulators that have roles as 'writers', 'readers' or 'editors' of DNA methylation and/or chromatin states. In this Review, we discuss how these mutations have the potential to deregulate hundreds of targeted genes genome wide. Elucidating these networks of epigenetic factors will provide mechanistic understanding of the interplay between genetic and epigenetic alterations, and will inform novel therapeutic strategies.
Asunto(s)
Cromatina , Epigénesis Genética , Genes Reguladores , Genoma , Mutación , Proteínas de Neoplasias/genética , Neoplasias/genética , Biología Computacional , Metilación de ADN , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismoRESUMEN
Periodontitis is a common oral disease that is characterized by infection and inflammation of the tooth supporting tissues. While its incidence is highly associated with outgrowth of the pathogenic microbiome, some patients show signs of predisposition and quickly fall into recurrence after treatment. Recent research using genetic associations of candidates as well as genome-wide analysis highlights that variations in genes related to the inflammatory response are associated with an increased risk of periodontitis. Intriguingly, some of the genes are regulated by epigenetic modifications, supposedly established and reprogrammed in response to environmental stimuli. In addition, the treatment with epigenetic drugs improves treatment of periodontitis in a mouse model. In this review, we highlight some of the recent progress identifying genetic factors associated with periodontitis and point to promising approaches in epigenetic research that may contribute to the understanding of molecular mechanisms involving different responses in individuals and the early detection of predispositions that may guide in future oral treatment and disease prevention.