RESUMEN
Inflammatory bowel disease (IBD) is the consequence of a complex interplay between environmental factors, like dietary habits, that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals. Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation, prognosis, and response to therapy. Consequently, it relates to gene expression control in response to environmental influences. The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats, refined sugars, starches and additives, as well as other environmental factors like sedentarism and excess bodyweight, influencing the promotion of gene expression and increasing DNA hypomethylation in IBD. As many genetic variants are now associated with Crohn's disease (CD), new therapeutic strategies targeting modifiable environmental triggers, such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens, are of growing interest in the current literature. Diet, as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD, provides novel insights into the pathophysiology of intestinal and extraintestinal inflammatory disorders.
Asunto(s)
Metilación de ADN , Dieta , Epigénesis Genética , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/inmunología , Dieta/efectos adversos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Conducta Alimentaria , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVE: To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR). METHODS: The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels. RESULTS: The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used. CONCLUSION: Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.
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Metilación de ADN , Janus Quinasa 2 , Leptina , Ratas Sprague-Dawley , Receptores de Leptina , Daño por Reperfusión , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Janus Quinasa 2/metabolismo , Ratas , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores de Leptina/metabolismo , Receptores de Leptina/genética , Masculino , Leptina/metabolismo , Células PC12 , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Caspasa 3/metabolismoRESUMEN
BACKGROUND: Although the clinical signs of inflammatory breast cancer (IBC) resemble acute inflammation, the role played by infiltrating immune and stromal cells in this aggressive disease is uncharted. The tumor microenvironment (TME) presents molecular alterations, such as epimutations, prior to morphological abnormalities. These changes affect the distribution and the intricate communication between the TME components related to cancer prognosis and therapy response. Herein, we explored the global DNA methylation profile of IBC and surrounding tissues to estimate the microenvironment cellular composition and identify epigenetically dysregulated markers. METHODS: We used the HiTIMED algorithm to deconvolve the bulk DNA methylation data of 24 IBC and six surrounding non-tumoral tissues (SNT) (GSE238092) and determine their cellular composition. The prognostic relevance of cell types infiltrating IBC and their relationship with clinicopathological variables were investigated. CD34 (endothelial cell marker) and CD68 (macrophage marker) immunofluorescence staining was evaluated in an independent set of 17 IBC and 16 non-IBC samples. RESULTS: We found lower infiltration of endothelial, stromal, memory B, dendritic, and natural killer cells in IBC than in SNT samples. Higher endothelial cell (EC) and stromal cell content were related to better overall survival. EC proportions positively correlated with memory B and memory CD8+ T infiltration in IBC. Immune and EC markers exhibited distinct DNA methylation profiles between IBC and SNT samples, revealing hypermethylated regions mapped to six genes (CD40, CD34, EMCN, HLA-G, PDPN, and TEK). We identified significantly higher CD34 and CD68 protein expression in IBC compared to non-IBC. CONCLUSIONS: Our findings underscored cell subsets that distinguished patients with better survival and dysregulated markers potentially actionable through combinations of immunotherapy and epigenetic drugs.
Asunto(s)
Metilación de ADN , Neoplasias Inflamatorias de la Mama , Microambiente Tumoral , Humanos , Metilación de ADN/genética , Microambiente Tumoral/genética , Femenino , Neoplasias Inflamatorias de la Mama/genética , Neoplasias Inflamatorias de la Mama/patología , Neoplasias Inflamatorias de la Mama/metabolismo , Resultado del Tratamiento , Persona de Mediana Edad , Pronóstico , Terapia Molecular Dirigida , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Diesel exhaust particles (DEP), which contain hazardous compounds, are emitted during the combustion of diesel. As approximately one-third of the vehicles worldwide use diesel, there are growing concerns about the risks posed by DEP to human health. Long-term exposure to DEP is associated with airway hyperresponsiveness, pulmonary fibrosis, and inflammation; however, the molecular mechanisms behind the effects of DEP on the respiratory tract are poorly understood. Such mechanisms can be addressed by examining transcriptional and DNA methylation changes. Although several studies have focused on the effects of short-term DEP exposure on gene expression, research on the transcriptional effects and genome-wide DNA methylation changes caused by long-term DEP exposure is lacking. Hence, in this study, we investigated transcriptional and DNA methylation changes in human adenocarcinoma alveolar basal epithelial A549 cells caused by prolonged exposure to DEP and determined whether these changes are concordant. RESULTS: DNA methylation analysis using the Illumina Infinium MethylationEPIC BeadChips showed that the methylation levels of DEP-affected CpG sites in A549 cells changed in a dose-dependent manner; the extent of change increased with increasing dose reaching the statistical significance only in samples exposed to 30 µg/ml DEP. Four-week exposure to 30 µg/ml of DEP significantly induced DNA hypomethylation at 24,464 CpG sites, which were significantly enriched for DNase hypersensitive sites, genomic regions marked by H3K4me1 and H3K27ac, and several transcription factor binding sites. In contrast, 9,436 CpG sites with increased DNA methylation levels were significantly overrepresented in genomic regions marked by H3K27me3 as well as H3K4me1 and H3K27ac. In parallel, gene expression profiling by RNA sequencing demonstrated that long-term exposure to DEP altered the expression levels of 2,410 genes, enriching 16 gene sets including Xenobiotic metabolism, Inflammatory response, and Senescence. In silico analysis revealed that the expression levels of 854 genes correlated with the methylation levels of the DEP-affected cis-CpG sites. CONCLUSIONS: To our knowledge, this is the first report of genome-wide transcriptional and DNA methylation changes and their associations in A549 cells following long-term exposure to DEP.
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Metilación de ADN , Transcriptoma , Emisiones de Vehículos , Humanos , Metilación de ADN/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Células A549 , Transcriptoma/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Islas de CpG , Material Particulado/toxicidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismoRESUMEN
To assess the diagnostic efficacy of SEPT9 along with PAX5 gene methylation detection in gastrointestinal cancer and precancerous lesions, the peripheral blood of 62 patients with gastric cancer (GC) and 60 patients with no evidence of disease (as the control group) were retrospectively collected. The methylation rates of PAX5 and SEPT9 gene promoters in blood samples of GC group were detected by PCR. At the same time, the differences in methylation rates of genes in the two groups were compared, and the predictive value of plasma methylation PAX5 and SEPT9 in GC was evaluated by receiver operating characteristic (ROC) curve. We found that there were 41 cases of methylated PAX5 gene promoter region and 39 cases of methylated SEPT9 gene promoter region in GC group. The control group contained 14 cases of PAX5 gene promoter methylation and 12 cases of RNF¹80 gene promoter methylation. The occurrence of PAX5 promoter methylation was correlated with age of GC patients. There were statistically significant differences in mSEPT9 gene in patients with different TNM stages. Kaplan-Meier survival curve analysis revealed that the three-year overall survival rate of GC patients with PAX5 methylation was lower than that of GC patients without PAX5 methylation. No significant difference was discovered in 3-year overall survival rate between GC patients with SEPT9 methylation and those without SEPT9 methylation. Combined detection could not improve the diagnostic value of GC, but could promote diagnosis sensitivity. In summary, the risk of PAX5 and SEPT9 gene methylation in GC patients presents higher when compared with healthy people. PAX5 gene methylation is closely related to age, while SEPT9 is closely related to tumor TNM stage, and PAX5 gene methylation can decrease the survival rate of GC patients. Detection of PAX5 gene methylation level can assist in evaluating the prognosis of GC patients.
Asunto(s)
Metilación de ADN , Factor de Transcripción PAX5 , Lesiones Precancerosas , Regiones Promotoras Genéticas , Septinas , Humanos , Septinas/genética , Metilación de ADN/genética , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Anciano , Lesiones Precancerosas/genética , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/patología , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/patología , Curva ROC , Estimación de Kaplan-Meier , Neoplasias Gástricas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Adulto , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Estadificación de NeoplasiasRESUMEN
Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, Ntotal = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90-1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R2 of 0.07 (95% CI: 0.05-0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97-6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
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Redes Neurales de la Computación , Fenotipo , Humanos , Estudios de Cohortes , Metilación de ADN/genética , Masculino , Femenino , Persona de Mediana Edad , Fumar/genética , Genómica/métodos , Adulto , Biología Computacional/métodos , Islas de CpG/genética , Anciano , MultiómicaRESUMEN
INTRODUCTION: Variation in DNA methylation (DNAm) in adipose tissue is associated with the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors. OBJECTIVES: To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans. METHODS: In the AAGMEx cohort (N = 256), plasma levels of metabolites were measured by untargeted liquid chromatography-mass spectrometry; adipose tissue DNAm and transcript levels were measured by reduced representation bisulfite sequencing, and expression microarray, respectively. RESULTS: Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (PFDR < 0.05, for BMI, SI, or Matsuda index) in AAGMEx. Methylation levels of 196, 116, and 180 CpG-sites were associated (P < 0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts, including genes in G-protein coupled receptor signaling pathway. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G-protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (ß = 1.87, P = 1.9 × 10-16) and SI (ß = -1.61, P = 2.49 × 10-5). CONCLUSION: Our study suggests that a subset of metabolites modulates the methylation levels of CpG sites in specific loci and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.
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Metilación de ADN , Epigénesis Genética , Resistencia a la Insulina , Obesidad , Humanos , Resistencia a la Insulina/genética , Obesidad/metabolismo , Obesidad/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , Regulación de la Expresión Génica , Tejido Adiposo/metabolismo , MetabolómicaRESUMEN
One of the main causes of cancer-related mortality for women worldwide is breast cancer (BC). The XRCC2 gene, essential for DNA repair, has been implicated in cancer susceptibility. This study aims to evaluate the association between XRCC2 and BC risk. The study was conducted at Zheen International Hospital in Erbil, Iraq, between 2021 and 2024 with a total of 88 samples, including 44 paired normal and cancer tissue samples. Mutation analysis was performed using Next-Generation Sequencing, coupled with in silico tools for variant impact prediction. Expression levels were assessed through RT-PCR, and methylation status was determined using methylation-sensitive restriction enzyme digestion PCR. The study identified seven inherited germline variants in the XRCC2 gene, with five of these mutations being Uncertain Significance, one being Likely Pathogenic, and one being Likely benign. RNA purity was found high with mean A260/280 ratios of 1.986 ± 0.097 in normal (N) and 1.963 ± 0.092 in tumor (T) samples. Tumor samples exhibited a higher RNA concentration (78.56 ± 40.87 ng/µL) than normal samples (71.44 ± 40.79 ng/µL). XRCC2 gene expression was significantly upregulated in tumor tissue, with marked increases in patients aged 40-55 and >56 years and in higher cancer grades (II and III) and invasive ductal carcinoma (p-values ranging from <0.0001 to 0.0392). DNA methylation rates in tumor tissues were low (7%), suggesting limited regulation by methylation. The study suggests that XRCC2 can be classified as an oncogene and that its structural investigation by targeted NGS and expression evaluation can be used as a potential biomarker in BC.
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Neoplasias de la Mama , Metilación de ADN , Proteínas de Unión al ADN , Multiómica , Adulto , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Genómica/métodos , Multiómica/métodos , Transcriptoma/genéticaRESUMEN
Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.
Asunto(s)
Neoplasias Encefálicas , Islas de CpG , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación de ADN/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Islas de CpG/genética , Niño , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Epigenoma , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Masculino , Telomerasa/genética , FemeninoRESUMEN
BACKGROUND: Patients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive. METHODS: The expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells. RESULTS: The expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by ß-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by ß-catenin activator BML-284, indicating that function of RASAL1 depends on ß-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and ß-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs. CONCLUSION: Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating ß-catenin both in vitro and in vivo.
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Coriocarcinoma , Metilación de ADN , Proteínas de Unión al ADN , Dioxigenasas , Resistencia a Antineoplásicos , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas , Humanos , Resistencia a Antineoplásicos/genética , Coriocarcinoma/metabolismo , Coriocarcinoma/patología , Coriocarcinoma/genética , Animales , Femenino , Ratones , Dioxigenasas/metabolismo , Dioxigenasas/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/metabolismo , Carcinogénesis/genética , EmbarazoRESUMEN
Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.
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Poli(ADP-Ribosa) Polimerasa-1 , Transcripción Genética , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Animales , Neoplasias/genética , Neoplasias/metabolismo , Regulación de la Expresión Génica , Metilación de ADN , Cromatina/metabolismoRESUMEN
Detection of important genes affecting lung adenocarcinoma (LUAD) is critical to finding effective therapeutic targets for this highly lethal cancer. However, many existing approaches have focused on single outcomes or phenotypic associations, which may not be as thorough as investigating molecular transcript levels within cells. In this article, we apply a novel multivariate rank-distance correlation-based gene selection procedure (MrDcGene) to LUAD multi-omics data downloaded from The Cancer Genome Atlas (TCGA). MrDcGene provides additional opportunities for detecting novel susceptibility genes as it leverages information from multiple platforms, while efficiently handling challenges such as high dimensionality, low signal-to-noise ratio, unknown distributions, and non-linear structures, etc. Notably, the MrDcGene method is able to detect two different scenarios, i.e., strong association strength with a few gene expressions and weak association strength with several gene expressions. After thoroughly exploring the association between gene expression (GE) and multiple other platforms, including reverse phase protein array (RPPA), miRNA, copy number variation (CNV) and DNA methylation (ME), we detect several novel genes that may play an important role in LUAD (ZNF133, CCDC159, YWHAZ, HNRNPR. ITPR2, PTHLH, and WIPI2). In addition, we quantitatively validate several other susceptibility genes that were reported in the literature using different methods and studies. The accuracy of the MrDcGene approach is theoretically assured and empirically demonstrated by the simulation studies.
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Adenocarcinoma del Pulmón , Variaciones en el Número de Copia de ADN , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Metilación de ADN , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Neoplasias Pulmonares/genética , Multiómica/métodosRESUMEN
BACKGROUND: Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation. RESULTS: A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03-3.19). CONCLUSIONS: Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival.
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Metilación de ADN , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Masculino , Femenino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Características del Vecindario , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estados Unidos/epidemiología , Factores Socioeconómicos , Características de la ResidenciaRESUMEN
Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.
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Ácidos Nucleicos Libres de Células , Islas de CpG , Fragmentación del ADN , Metilación de ADN , Neoplasias , Humanos , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Animales , Ratones , Islas de CpG/genética , Neoplasias/genética , Epigénesis Genética , Femenino , Isocitrato Deshidrogenasa/genética , Masculino , Regulación Neoplásica de la Expresión GénicaRESUMEN
Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8+T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.
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Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral/inmunología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Animales , Agotamiento de Células TRESUMEN
Lynch syndrome (LS) is a prevalent genetic condition associated with colorectal cancer (CRC). Accurate identification of LS patients is challenging, and a universal tumor screening approach has been recommended. We present the methodology and results of universal LS screening in our hospital's Pathology Department. This retrospective study analyzed CRC tumors from a 5-year period (2017-2021). Immunohistochemistry was used to assess MMR protein expression, followed by BRAF V600E analysis and MLH1 promoter methylation. Statistical analysis examined associations between clinicopathologic variables MMR status and LS-suspected tumors. The study analyzed 939 colorectal carcinomas, with 8.7% exhibiting mismatch repair (MMR) deficiency, significantly lower than previous research. After applying the algorithm, 24 LS-suspected cases were identified, accounting for 2.6% of tested patients and 29.3% of MMR-deficient tumors. Our study establishes the feasibility of universal testing for all new cases of CRC in detecting individuals at risk for LS, even in the absence of clinical information. To gain a comprehensive understanding of the MMR status in our population, further investigations are warranted.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Homólogo 1 de la Proteína MutL , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Masculino , Persona de Mediana Edad , Portugal/epidemiología , Estudios Retrospectivos , Anciano , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Neoplasias Colorrectales/diagnóstico , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Metilación de ADN , Detección Precoz del Cáncer , InmunohistoquímicaRESUMEN
Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency, centromeric instability, and facial anomalies syndrome, characterized by DNA hypomethylation at heterochromatin. It remains unclear why CDCA7-HELLS is the sole nucleosome remodeling complex whose deficiency abrogates the maintenance of DNA methylation. We here identify the unique zinc-finger domain of CDCA7 as an evolutionarily conserved hemimethylation-sensing zinc finger (HMZF) domain. Cryo-electron microscopy structural analysis of the CDCA7-nucleosome complex reveals that the HMZF domain can recognize hemimethylated CpG in the outward-facing DNA major groove within the nucleosome core particle, whereas UHRF1, the critical activator of the maintenance methyltransferase DNMT1, cannot. CDCA7 recruits HELLS to hemimethylated chromatin and facilitates UHRF1-mediated H3 ubiquitylation associated with replication-uncoupled maintenance DNA methylation. We propose that the CDCA7-HELLS nucleosome remodeling complex assists the maintenance of DNA methylation on chromatin by sensing hemimethylated CpG that is otherwise inaccessible to UHRF1 and DNMT1.
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Proteínas Potenciadoras de Unión a CCAAT , Metilación de ADN , Nucleosomas , Ubiquitina-Proteína Ligasas , Humanos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Nucleosomas/metabolismo , Nucleosomas/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Microscopía por Crioelectrón , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/química , Islas de CpG , Ubiquitinación , Evolución Molecular , ADN/metabolismo , ADN/química , ADN/genética , Dedos de Zinc , Cromatina/metabolismo , Cromatina/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN Helicasas/metabolismo , ADN Helicasas/genética , ADN Helicasas/química , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/química , Eucariontes/genética , Eucariontes/metabolismo , Unión Proteica , Histonas/metabolismo , Histonas/genética , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/químicaRESUMEN
BACKGROUND: In this study, we present a novel method for reference-based cell deconvolution using data from DNA methylation arrays. Different from existing methods like IDOL-Ext, which operate on probe-level data, our approach represents features in the principal component analysis (PCA) space for cell type deconvolution. RESULTS: Our method's accuracy in estimating cell compositions is validated across various public datasets, including blood samples from glioma patients. It demonstrates precision comparable to IDOL-Ext, with R2 values ranging from 0.73 to 0.99 for most cell types, while offering improved discrimination between similar cell types, particularly T cell subtypes in glioma patient samples (R2 0.42-0.75 vs. 0.36-0.66 for IDOL-Ext). However, both methods showed lower accuracy for certain cell types, such as memory CD8 T cells in glioma patients (R2 0.42 vs. 0.36 for IDOL-Ext), highlighting the challenges in distinguishing closely related cell populations. We have made this method available as an R package "BloodCellDecon" on GitHub. CONCLUSIONS: Our study confirms the efficacy of cell type deconvolution in PCA space. The results indicate wide-ranging applicability and potential for adaptation to other forms of genomic data.
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Metilación de ADN , Glioma , Análisis de Componente Principal , Humanos , Glioma/genética , Glioma/patologíaRESUMEN
BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks. METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR). RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007). CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.
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Epigénesis Genética , Estudio de Asociación del Genoma Completo , Neoplasias Hematológicas , Análisis de la Aleatorización Mendeliana , Telómero , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Neoplasias Hematológicas/genética , Epigénesis Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Telómero/genética , Metilación de ADN/genética , Femenino , Masculino , Homeostasis del Telómero/genética , Acortamiento del Telómero/genéticaRESUMEN
Kirsten Rat Sarcoma (KRAS) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti-CDKN2A therapy with Villosol in KRAS-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.