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1.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803872

RESUMEN

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a highly aggressive malignancy, with poorer prognosis in infants than in adults. A genetic signature has been associated with this outcome but, remarkably, leukemogenesis is commonly triggered by genetic alterations of embryonic origin that involve the deregulation of chromatin remodelers. This review considers in depth how the alteration of epigenetic profiles (at DNA and histone levels) induces an aberrant phenotype in B lymphocyte progenitors by modulating the oncogenic drivers and tumor suppressors involved in key cancer hallmarks. DNA methylation patterns have been widely studied in BCP-ALL and their correlation with survival has been established. However, the effect of methylation on histone residues can be very different. For instance, methyltransferase KMT2A gene participates in chromosomal rearrangements with several partners, imposing an altered pattern of methylated H3K4 and H3K79 residues, enhancing oncogene promoter activation, and conferring a worse outcome on affected infants. In parallel, acetylation processes provide an additional layer of epigenetic regulation and can alter the chromatin conformation, enabling the binding of regulatory factors. Therefore, an integrated knowledge of all epigenetic disorders is essential to understand the molecular basis of BCP-ALL and to identify novel entry points that can be exploited to improve therapeutic options and disease prognosis.


Asunto(s)
Epigénesis Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Metilación de ADN/genética , Regulación Leucémica de la Expresión Génica , Histonas/metabolismo , Humanos , Lactante , Procesamiento Proteico-Postraduccional
2.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802562

RESUMEN

VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 × 10-4); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.


Asunto(s)
Metilación de ADN/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Islas de CpG/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sitios de Carácter Cuantitativo/genética
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802702

RESUMEN

Our previous study demonstrated that the glutathione S-transferase Mu 5 (GSTM5) gene is highly CpG-methylated in bladder cancer cells and that demethylation by 5-aza-dC activates GSTM5 gene expression. The aim of the present study was to investigate the role of GSTM5 in bladder cancer. The levels of GSTM5 gene expression and DNA methylation were analyzed in patients with bladder cancer, and functional studies of GSTM5 were conducted using GSTM5 overexpression in cultured bladder cancer cells. Clinical analysis revealed that the GSTM5 mRNA expression was lower in bladder cancer tissues than in normal tissues and that the level of GSTM5 DNA methylation was higher in bladder cancer tissues than in normal urine pellets. Overexpression of GSTM5 decreased cell proliferation, migration and colony formation capacity. Glutathione (GSH) assay results indicated that cellular GSH concentration was decreased by GSTM5 expression and that GSH supplementation reversed the decrease in proliferation and migration of cells overexpressing GSTM5. By contrast, a GSH synthesis inhibitor significantly decreased 5637 cell GSH levels, survival and migration. Furthermore, GSTM5 overexpression inhibited the adhesion of cells to the extracellular matrix protein fibronectin. To elucidate the effect of GSTM5 on anticancer drugs used to treat bladder cancer, cellular viability was compared between cells with or without GSTM5 overexpression. GSTM5-overexpressed cells showed no significant change in the cytotoxicity of cisplatin or mitomycin C in 5637, RT4 and BFTC 905 cells. Though a degree of resistance to doxorubicin was noted in 5637 cells overexpressing GSTM5, no such resistance was observed in RT4 and BFTC 905 cells. In summary, GSTM5 plays a tumor suppressor role in bladder cancer cells without significantly affecting chemoresistance to cisplatin and mitomycin C, and the cellular GSH levels highlight a key mechanism underlying the cancer inhibition effect of GSTM5. These findings suggest that low gene expression and high DNA methylation levels of GSTM5 may act as tumor markers for bladder cancer.


Asunto(s)
Antineoplásicos/metabolismo , Biomarcadores de Tumor/metabolismo , Glutatión Transferasa/metabolismo , Neoplasias de la Vejiga Urinaria/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Butionina Sulfoximina/farmacología , Adhesión Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cisplatino/farmacología , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/farmacología , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Caracteres Sexuales , Neoplasias de la Vejiga Urinaria/genética
4.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804149

RESUMEN

In the last few decades, the newly emerging field of epigenetic regulation of glycosylation acquired more importance because it is unraveling physiological and pathological mechanisms related to glycan functions. Glycosylation is a complex process in which proteins and lipids are modified by the attachment of monosaccharides. The main actors in this kind of modification are the glycoenzymes, which are translated from glycosylation-related genes (or glycogenes). The expression of glycogenes is regulated by transcription factors and epigenetic mechanisms (mainly DNA methylation, histone acetylation and noncoding RNAs). This review focuses only on these last ones, in relation to cancer and other diseases, such as inflammatory bowel disease and IgA1 nephropathy. In fact, it is clear that a deeper knowledge in the fine-tuning of glycogenes is essential for acquiring new insights in the glycan field, especially if this could be useful for finding novel and personalized therapeutics.


Asunto(s)
Epigénesis Genética/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional/genética , ARN no Traducido/genética , Acetilación , Metilación de ADN/genética , Glicosilación , Humanos , Inmunoglobulina A/genética , Neoplasias/metabolismo , Polisacáridos/genética
5.
Medicine (Baltimore) ; 100(16): e25541, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879700

RESUMEN

ABSTRACT: Thyroid cancer is a common endocrine malignancy; however, surgery remains its primary treatment option. A novel targeted drug for the development and application of targeted therapy in thyroid cancer treatment remain underexplored.We obtained RNA sequence data of thyroid cancer from The Cancer Genome Atlas database and identified differentially expressed genes (DEGs). Then, we constructed co-expression network with DEGs and combined it with differentially methylation analysis to screen the key genes in thyroid cancer. PockDrug-Server, an online tool, was applied to predict the druggability of the key genes. Finally, we constructed protein-protein interaction (PPI) network to observe potential targeted drugs for thyroid cancer.We identified 3 genes correlated with altered DNA methylation level and oncogenesis of thyroid cancer. According to the druggable analysis and PPI network, we predicted TRAF2 and NCK-interacting protein kinase (TNIK) sever as the drug targeted for thyroid cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that genes in protein-protein interaction network of TNIK enriched in mitogen-activated protein kinase signaling pathway. For drug repositioning, we identified a targeted drug of genes in PPI network.Our study provides a bioinformatics method for screening drug targets and provides a theoretical basis for thyroid cancer targeted therapy.


Asunto(s)
Desarrollo de Medicamentos/métodos , Proteínas Serina-Treonina Quinasas/genética , Factor 2 Asociado a Receptor de TNF/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Biología Computacional/métodos , Metilación de ADN/genética , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Humanos , Sistema de Señalización de MAP Quinasas/genética , Mapas de Interacción de Proteínas/genética
6.
Medicine (Baltimore) ; 100(16): e25552, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879706

RESUMEN

ABSTRACT: The level of long interspersed nuclear element-1 (LINE-1) methylation, representing the global deoxyribonucleic acid methylation level, could contribute to the prognosis of cancer via the activation of oncogenes. This study was performed to evaluate the prognostic implications of LINE-1 hypomethylation in patients with hepatocellular carcinoma (HCC) and the possible mechanisms related to oncogene activation.Seventy-seven HCC patients between October 2014 and September 2015 were enrolled in this prospective study. Quantitative pyrosequencing was performed to assess the LINE-1 methylation level of HCC and matched non-HCC tissue samples. The expression of suppression of tumorigenicity 18 was measured by immunohistochemistry and its correlation with LINE-1 methylation levels was examined.LINE-1 was significantly hypomethylated in the HCC tissue compared with the matched nontumor tissue (64.0 ± 11.6% vs 75.6 ±â€Š4.0%, P < .001). LINE-1 hypomethylation was an independent risk factor for overall survival (hazard ratio = 27.291, P = .032) and disease progression (hazard ratio = 5.298, P = .005). The expression of suppression of tumorigenicity 18 was higher in the hypomethylated LINE-1 HCC tissue than the hypermethylated LINE-1 tumor tissue (P = .030).LINE-1 hypomethylation may serve as a potential prognostic marker for patients with HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Metilación de ADN/genética , Neoplasias Hepáticas/genética , Elementos de Nucleótido Esparcido Largo/genética , Proteínas Represoras/metabolismo , Biomarcadores de Tumor/genética , Biopsia , Carcinogénesis/genética , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Oncogenes/genética , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos
7.
Medicine (Baltimore) ; 100(12): e25093, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761671

RESUMEN

ABSTRACT: Based on the Thompson classification of intervertebral discs (IVDs), we systematically analyzed gene expression differences between severely degenerated and mildly degenerated IVDs and explored the underlying molecular mechanisms using bioinformatics methods and multichip integration. We used multiomics analysis, includes mRNA microarray and methylation chips, to explore the genetic network and mechanisms of lumbar disc herniation (LDH). Subsequently, the Combat function of the R language SVA package was applied to eliminate heterogeneity between the gene expression data. And the protein-protein interaction (PPI) network, gene ontology (GO), and molecular pathways were used to constructs the mechanisms network. Consequently, we obtained 149 differentially expressed genes. Related molecular pathways are the following: ribosome activity, oxidative phosphorylation, extracellular matrix response. Besides, through PPI network analysis, genes with higher connectivity such as UBA52, RPLP0, RPL3, RPLP2, and RPL27 were also identified, suggesting that they play important regulatory roles in the complex network associated with LDH. Additionally, cg12556991 (RPL27) and cg06852319 (RPLP0) were found to be LDH-related candidate DNA methylation modification sites in the IVDs tissue of LDH patients. In conclusions, ribosome activity, oxidative phosphorylation, and extracellular matrix response may be potential molecular mechanisms underlying LDH, while hub genes involved in UBA52, RPLP0, RPL3, RPLP2, and RPL27, and candidate DNA methylation modification sites of cg12556991and cg06852319 are likely key regulators in the development of LDH.


Asunto(s)
Metilación de ADN/genética , Matriz Extracelular/genética , Desplazamiento del Disco Intervertebral/genética , Fosforilación/genética , Proteínas Ribosómicas/genética , Biología Computacional , Expresión Génica/genética , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes/genética , Humanos , Vértebras Lumbares/metabolismo , Análisis por Micromatrices , Mapas de Interacción de Proteínas/genética , ARN Mensajero/metabolismo
8.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669837

RESUMEN

We established the following two variants of the MOLM-13 human acute myeloid leukemia (AML) cell line: (i) MOLM-13/DAC cells are resistant to 5-aza-2'-deoxycytidine (DAC), and (ii) MOLM-13/AZA are resistant to 5-azacytidine (AZA). Both cell variants were obtained through a six-month selection/adaptation procedure with a stepwise increase in the concentration of either DAC or AZA. MOLM-13/DAC cells are resistant to DAC, and MOLM-13/AZA cells are resistant to AZA (approximately 50-fold and 20-fold, respectively), but cross-resistance of MOLM-13/DAC to AZA and of MOLM-13/AZA to DAC was not detected. By measuring the cell retention of fluorescein-linked annexin V and propidium iodide, we showed an apoptotic mode of death for MOLM-13 cells after treatment with either DAC or AZA, for MOLM-13/DAC cells after treatment with AZA, and for MOLM-13/AZA cells after treatment with DAC. When cells progressed to apoptosis, via JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) assay, we detected a reduction in the mitochondrial membrane potential. Furthermore, we characterized promoter methylation levels for some genes encoding proteins regulating apoptosis and the relation of this methylation to the expression of the respective genes. In addition, we focused on determining the expression levels and activity of intrinsic and extrinsic apoptosis pathway proteins.


Asunto(s)
Apoptosis , Metilación de ADN/genética , Resistencia a Antineoplásicos , Transducción de Señal , Apoptosis/efectos de los fármacos , Apoptosis/genética , Azacitidina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Metilación de ADN/efectos de los fármacos , Decitabina/farmacología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Biológicos , Necrosis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regiones Promotoras Genéticas , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo
9.
Nat Commun ; 12(1): 1556, 2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33692344

RESUMEN

The differentiation of human blood monocytes (MO), the post-mitotic precursors of macrophages (MAC) and dendritic cells (moDC), is accompanied by the active turnover of DNA methylation, but the extent, consequences and mechanisms of DNA methylation changes remain unclear. Here, we profile and compare epigenetic landscapes during IL-4/GM-CSF-driven MO differentiation across the genome and detect several thousand regions that are actively demethylated during culture, both with or without accompanying changes in chromatin accessibility or transcription factor (TF) binding. We further identify TF that are globally associated with DNA demethylation processes. While interferon regulatory factor 4 (IRF4) is found to control hallmark dendritic cell functions with less impact on DNA methylation, early growth response 2 (EGR2) proves essential for MO differentiation as well as DNA methylation turnover at its binding sites. We also show that ERG2 interacts with the 5mC hydroxylase TET2, and its consensus binding sequences show a characteristic DNA methylation footprint at demethylated sites with or without detectable protein binding. Our findings reveal an essential role for EGR2 as epigenetic pioneer in human MO and suggest that active DNA demethylation can be initiated by the TET2-recruiting TF both at stable and transient binding sites.


Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Monocitos/metabolismo , Sitios de Unión , Células Cultivadas , Secuenciación de Inmunoprecipitación de Cromatina , Desmetilación del ADN , Metilación de ADN/genética , Metilación de ADN/fisiología , Proteína 2 de la Respuesta de Crecimiento Precoz/química , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Humanos , Immunoblotting , Inmunoprecipitación , Espectrometría de Masas , Unión Proteica , RNA-Seq
10.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33669975

RESUMEN

The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.


Asunto(s)
Metilación de ADN/genética , Placenta/metabolismo , Adulto , Femenino , Humanos , Recién Nacido , Elementos de Nucleótido Esparcido Largo/genética , Anotación de Secuencia Molecular , Embarazo , Análisis de Componente Principal
11.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670079

RESUMEN

Type 2 diabetes (T2D) typically occurs in the setting of obesity and insulin resistance, where hyperglycemia is associated with decreased pancreatic ß-cell mass and function. Loss of ß-cell mass has variably been attributed to ß-cell dedifferentiation and/or death. In recent years, it has been proposed that circulating epigenetically modified DNA fragments arising from ß cells might be able to report on the potential occurrence of ß-cell death in diabetes. Here, we review published literature of DNA-based ß-cell death biomarkers that have been evaluated in human cohorts of islet transplantation, type 1 diabetes, and obesity and type 2 diabetes. In addition, we provide new data on the applicability of one of these biomarkers (cell free unmethylated INS DNA) in adult cohorts across a spectrum from obesity to T2D, in which no significant differences were observed, and compare these findings to those previously published in youth cohorts where differences were observed. Our analysis of the literature and our own data suggest that ß-cell death may occur in subsets of individuals with obesity and T2D, however a more sensitive method or refined study designs are needed to provide better alignment of sampling with disease progression events.


Asunto(s)
Biomarcadores/metabolismo , Ácidos Nucleicos Libres de Células/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Muerte Celular , Metilación de ADN/genética , Humanos
12.
Nat Protoc ; 16(4): 2131-2157, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33686219

RESUMEN

The stable maintenance of DNA methylation patterns during mitotic cell division is crucial for cell identity. Precisely determining the maintenance kinetics and dissecting the exact contributions of relevant regulators requires a method to accurately measure parent and daughter strand DNA methylation at the same time, ideally at the single-molecule level. Recently, we developed a method referred to as Hammer-seq (hairpin-assisted mapping of methylation of replicated DNA) that fulfils the above criteria. This method integrates 5-ethynyl-2'-deoxyuridine (EdU) labeling of replicating DNA, biotin conjugation and streptavidin-based affinity purification, and whole-genome hairpin bisulfite sequencing technologies. Hammer-seq offers the unique advantage of simultaneously measuring the methylation status of parent and daughter strands within a single DNA molecule, which makes it possible to determine maintenance kinetics across various genomic regions without averaging effects from bulk measurements and to assess de novo methylation events that accompany methylation maintenance. Importantly, when combined with mutant cell lines in which mechanisms of interest are disrupted, Hammer-seq can be applied to determine the functional contributions of potential regulators to methylation maintenance, with accurate kinetics information that cannot be acquired with other currently available methods. Hammer-seq library preparation requires ~100 ug EdU-labeled genomic DNA as input (~15 million mammalian cells). The whole protocol, from pulse labeling to library construction, can be completed within 2-3 d, depending on the chasing time.


Asunto(s)
Metilación de ADN/genética , Replicación del ADN/genética , Imagen Individual de Molécula , Biotina/metabolismo , Química Clic , ADN/metabolismo , Células HeLa , Humanos , Ligandos , Sonicación
13.
Microbiome ; 9(1): 57, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637135

RESUMEN

BACKGROUND: Plants are naturally associated with root microbiota, which are microbial communities influential to host fitness. Thus, it is important to understand how plants control root microbiota. Epigenetic factors regulate the readouts of genetic information and consequently many essential biological processes. However, it has been elusive whether RNA-directed DNA methylation (RdDM) affects root microbiota assembly. RESULTS: By applying 16S rRNA gene sequencing, we investigated root microbiota of Arabidopsis mutants defective in the canonical RdDM pathway, including dcl234 that harbors triple mutation in the Dicer-like proteins DCL3, DCL2, and DCL4, which produce small RNAs for RdDM. Alpha diversity analysis showed reductions in microbe richness from the soil to roots, reflecting the selectivity of plants on root-associated bacteria. The dcl234 triple mutation significantly decreases the levels of Aeromonadaceae and Pseudomonadaceae, while it increases the abundance of many other bacteria families in the root microbiota. However, mutants of the other examined key players in the canonical RdDM pathway showed similar microbiota as Col-0, indicating that the DCL proteins affect root microbiota in an RdDM-independent manner. Subsequently gene analysis by shotgun sequencing of root microbiome indicated a selective pressure on microbial resistance to plant defense in the dcl234 mutant. Consistent with the altered plant-microbe interactions, dcl234 displayed altered characters, including the mRNA and sRNA transcriptomes that jointly highlighted altered cell wall organization and up-regulated defense, the decreased cellulose and callose deposition in root xylem, and the restructured profile of root exudates that supported the alterations in gene expression and cell wall modifications. CONCLUSION: Our findings demonstrate an important role of the DCL proteins in influencing root microbiota through integrated regulation of plant defense, cell wall compositions, and root exudates. Our results also demonstrate that the canonical RdDM is dispensable for Arabidopsis root microbiota. These findings not only establish a connection between root microbiota and plant epigenetic factors but also highlight the complexity of plant regulation of root microbiota. Video abstract.


Asunto(s)
Arabidopsis/metabolismo , Arabidopsis/microbiología , Metilación de ADN/genética , Microbiota , Raíces de Plantas/microbiología , ARN de Planta , Ribonucleasa III/metabolismo , Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas/genética , Microbiota/genética , Raíces de Plantas/genética , ARN Ribosómico 16S/genética , Ribonucleasa III/genética
14.
Nat Commun ; 12(1): 1226, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33619257

RESUMEN

The goal of the National Cancer Institute's (NCI's) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive ( https://gdc.cancer.gov/ ).


Asunto(s)
Análisis de Datos , Bases de Datos Genéticas , Genómica , Secuencia de Bases , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Regulación de la Expresión Génica , Genoma Humano , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Mutación/genética , National Cancer Institute (U.S.) , RNA-Seq , Reproducibilidad de los Resultados , Estados Unidos , Virus/genética
15.
J Clin Neurosci ; 85: 115-121, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33581781

RESUMEN

BACKGROUND: Grade 3 gliomas are aggressive primary brain tumors. Promoter methylation of methyl guanine methyl transferase (MGMT) has been associated with a favorable prognosis in patients with glioblastoma, but the impact of MGMT promoter methylation in patients with grade 3 gliomas is less clear. The purpose of the present study was to evaluate the utilization of MGMT testing in patients with Grade 3 glioma, as well its prognostic and predictive value. METHODS: The National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade 3 glioma without 1p19q codeletion. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. RESULTS: Of 20,488 total patients, 1,209 (5.0%) had MGMT testing. Of these patients, 561 (46.4%) were MGMT methylated (mMGMT), and 648 (53.6%) were MGMT unmethylated (uMGMT). mMGMT patients experienced greater median overall survival (OS) than both uMGMT patients as well as patients with no MGMT status reported (p < 0.05 for both). mMGMT was associated with improved OS for patients receiving adjuvant chemoradiation or adjuvant radiation, but not for patients receiving adjuvant chemotherapy or no adjuvant treatment. CONCLUSIONS: This is the largest study to date describing the utilization of and outcomes for mMGMT patients with grade 3 glioma. The present results demonstrate that mMGMT is a prognostic factor and possibly a predictive biomarker, and is currently under-utilized within the US. MGMT methylation status could be used to risk-stratify and select patients for treatment intensification. IMPORTANCE OF STUDY: The present study is the largest of its kind to examine the prognostic and predictive impact of MGMT methylation (mMGMT) amongst patients with Grade 3 Glioma. The results suggest that mMGMT is prognostic, as amongst all patients, mMGMT was associated with improved overall survival. These results also suggest that mMGMT is predictive, as patients treated with adjuvant chemoradiation or adjuvant radiation therapy did have improved overall survival with mMGMT, though there was no difference in overall survival observes amongst patients receiving adjuvant chemotherapy or those patients receiving no adjuvant treatment. The study also found that only 5% of patients nationwide with Grade 3 Glioma are tested for MGMT.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioma/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Metilación de ADN/genética , Femenino , Glioma/mortalidad , Glioma/patología , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas/genética
16.
Life Sci ; 271: 119186, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577852

RESUMEN

Myocardial fibrosis (MF) is a reactive remodeling process in response to myocardial injury. It is mainly manifested by the proliferation of cardiac muscle fibroblasts and secreting extracellular matrix (ECM) proteins to replace damaged tissue. However, the excessive production and deposition of extracellular matrix, and the rising proportion of type I and type III collagen lead to pathological fibrotic remodeling, thereby facilitating the development of cardiac dysfunction and eventually causing heart failure with heightened mortality. Currently, the molecular mechanisms of MF are still not fully understood. With the development of epigenetics, it is found that epigenetics controls the transcription of pro-fibrotic genes in MF by DNA methylation, histone modification and noncoding RNAs. In this review, we summarize and discuss the research progress of the mechanisms underlying MF from the perspective of epigenetics, including the newest m6A modification and crosstalk between different epigenetics in MF. We also offer a succinct overview of promising molecules targeting epigenetic regulators, which may provide novel therapeutic strategies against MF.


Asunto(s)
Cardiomiopatías/genética , Cardiomiopatías/patología , Epigénesis Genética/genética , Miocardio/patología , Remodelación Ventricular/genética , Animales , Cardiomiopatías/terapia , Metilación de ADN/genética , Fibrosis/genética , Fibrosis/patología , Fibrosis/terapia , Humanos
17.
ACS Appl Mater Interfaces ; 13(5): 6043-6052, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33525876

RESUMEN

DNA methylation is a kind of a crucial epigenetic marker orchestrating gene expression, molecular function, and cellular phenotype. However, manipulating the methylation status of specific genes remains challenging. Here, a clustered regularly interspaced palindromic repeats-Cas9-based near-infrared upconversion-activated DNA methylation editing system (CNAMS) was designed for the optogenetic editing of DNA methylation. The fusion proteins of photosensitive CRY2PHR, the catalytic domain of DNMT3A or TET1, and the fusion proteins for CIBN and catalytically inactive Cas9 (dCas9) were engineered. The CNAMS could control DNA methylation editing in response to blue light, thus allowing methylation editing in a spatiotemporal manner. Furthermore, after combination with upconversion nanoparticles, the spectral sensitivity of DNA methylation editing was extended from the blue light to near-infrared (NIR) light, providing the possibility for remote DNA methylation editing. These results demonstrated a meaningful step forward toward realizing the specific editing of DNA methylation, suggesting the wide utility of our CNAMS for functional studies on epigenetic regulation and potential therapeutic strategies for related diseases.


Asunto(s)
Proteína 9 Asociada a CRISPR/genética , Sistemas CRISPR-Cas/genética , Edición Génica , Técnicas Genéticas , Rayos Infrarrojos , Neoplasias de la Tiroides/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Apoptosis/genética , Proteína 9 Asociada a CRISPR/metabolismo , Supervivencia Celular , Células Cultivadas , Metilación de ADN/genética , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Tamaño de la Partícula , Propiedades de Superficie , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia
18.
Nat Commun ; 12(1): 1286, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627650

RESUMEN

DNA methylation (5mC) is central to cellular identity. The global erasure of 5mC from the parental genomes during preimplantation mammalian development is critical to reset the methylome of gametes to the cells in the blastocyst. While active and passive modes of demethylation have both been suggested to play a role in this process, the relative contribution of these two mechanisms to 5mC erasure remains unclear. Here, we report a single-cell method (scMspJI-seq) that enables strand-specific quantification of 5mC, allowing us to systematically probe the dynamics of global demethylation. When applied to mouse embryonic stem cells, we identified substantial cell-to-cell strand-specific 5mC heterogeneity, with a small group of cells displaying asymmetric levels of 5mCpG between the two DNA strands of a chromosome suggesting loss of maintenance methylation. Next, in preimplantation mouse embryos, we discovered that methylation maintenance is active till the 16-cell stage followed by passive demethylation in a fraction of cells within the early blastocyst at the 32-cell stage of development. Finally, human preimplantation embryos qualitatively show temporally delayed yet similar demethylation dynamics as mouse embryos. Collectively, these results demonstrate that scMspJI-seq is a sensitive and cost-effective method to map the strand-specific genome-wide patterns of 5mC in single cells.


Asunto(s)
Desmetilación del ADN , Metilación de ADN/fisiología , Animales , Blastocisto/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/deficiencia , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN/genética , Desarrollo Embrionario/genética , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Femenino , Humanos , Ratones , Ratones Noqueados , Embarazo
19.
Nat Commun ; 12(1): 1247, 2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33623021

RESUMEN

Extensive epigenetic reprogramming occurs during preimplantation embryo development. However, it remains largely unclear how the drastic epigenetic reprogramming contributes to transcriptional regulatory network during this period. Here, we develop a single-cell multiomics sequencing technology (scNOMeRe-seq) that enables profiling of genome-wide chromatin accessibility, DNA methylation and RNA expression in the same individual cell. We apply this method to depict a single-cell multiomics map of mouse preimplantation development. We find that genome-wide DNA methylation remodeling facilitates the reconstruction of genetic lineages in early embryos. Further, we construct a zygotic genome activation (ZGA)-associated regulatory network and reveal coordination among multiple epigenetic layers, transcription factors and repeat elements that instruct proper ZGA. Cell fates associated cis-regulatory elements are activated stepwise in post-ZGA stages. Trophectoderm (TE)-specific transcription factors play dual roles in promoting the TE program while repressing the inner cell mass (ICM) program during the ICM/TE separation.


Asunto(s)
Blastocisto/metabolismo , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Genómica , Análisis de la Célula Individual , Alelos , Animales , Linaje de la Célula/genética , Cromatina/metabolismo , Metilación de ADN/genética , Ectodermo/citología , Femenino , Masculino , Ratones , Filogenia , Regiones Promotoras Genéticas , Cigoto/metabolismo
20.
Cancer Sci ; 112(4): 1644-1654, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33576114

RESUMEN

The clinical efficacy of DNA cytology test (CY) in gastric cancer (GC) has been retrospectively proposed using cancer-specific methylation of cysteine dioxygenase type 1 (CDO1). We confirmed the clinical utility of DNA CY in a prospective cohort. Four hundred GC samples were prospectively collected for washing cytology (UMIN000026191), and detection of the DNA methylation of CDO1 was assessed by quantitative methylation-specific PCR in the sediments. Endpoint was defined as the match rate between conventional CY1 and DNA CY1 (diagnostic sensitivity), and the DNA CY0 rate (diagnostic specificity) in pStage IA. DNA CY1 was detected in 45 cases (12.5%), while CY1 was seen in 31 cases (8.6%) of 361 chemotherapy-naïve samples, where the sensitivity and specificity of the DNA CY in the peritoneal solutions were 74.2% and 96.5%, respectively. The DNA CY was positive for 3.5/0/4.9/11.4/58.8% in pStage IA/IB/II/III/IV, respectively (P < .01). In the multivariate analysis, DNA CY1 was independently correlated with pathological tumor depth (pT) (P = .0012), female gender (P = .0099), CY1 (P = .0135), P1 (P = .019), and carcinoembryonic antigen (CEA) (P = .036). The combination of DNA CY1 and P factor nearly all covered the potential peritoneal dissemination (P1 and/or CY1 and/or DNA CY1) (58/61:95.1%). DNA CY1 had a significantly poorer prognosis than DNA CY0 in GC patients (P < .0001). DNA CY1 detected by CDO1 promoter DNA methylation has a great value to detect minimal residual disease of the peritoneum in GC clinics, representing poor prognosis as a novel single DNA marker.


Asunto(s)
Líquido Ascítico/patología , ADN/genética , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/patología , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Anciano , Biomarcadores de Tumor/genética , Cisteína-Dioxigenasa/genética , Citodiagnóstico/métodos , Metilación de ADN/genética , Femenino , Humanos , Masculino , Estadificación de Neoplasias/métodos , Neoplasias Peritoneales/genética , Peritoneo/patología , Pronóstico , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Neoplasias Gástricas/genética
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