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1.
Anticancer Res ; 39(10): 5381-5391, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570433

RESUMO

BACKGROUND/AIM: Long noncoding RNAs (lncRNAs) are noncoding transcripts that are >200 nucleotides in length. However, the biological functions and regulation mechanisms of lncRNAs in gastric carcinogenesis remain unknown. MATERIALS AND METHODS: The expression levels of Linc00472 were analyzed by real-time PCR. The DNA methylation status was assessed using Combined Bisulfite Restriction Analysis (COBRA). The biological role of Linc00472 was assessed in AGS cells with Linc00472 overexpression. RESULTS: Using the next-generation sequencing approach, we identified DNA methylation-associated lncRNAs in gastric cancer cells. Among them, the expression level of Linc00472 significantly decreased in gastric cancer tissues compared to adjacent normal tissues. Furthermore, we observed a more frequent hypermethylation of CpG islands upstream of Linc00472 in gastric cancer tissues. Ectopic Linc00472 expression could significantly inhibit gastric cancer cell growth and migration. CONCLUSION: Epigenetically regulated Linc00472 expression plays a crucial role in modulating gastric cancer cell growth and motility.


Assuntos
Metilação de DNA/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ilhas de CpG/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos
2.
Adv Exp Med Biol ; 1178: 175-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493228

RESUMO

A global DNA hypomethylation and local changes in the methylation levels of specific DNA loci occur during aging in mammals. Global hypomethylation mainly affects highly methylated repeat sequences, such as transposable elements; it is an essentially stochastic process usually referred to as "epigenetic drift." Specific changes in DNA methylation affect various genome sequences and could be either hypomethylation or hypermethylation, but the prevailing tendencies are hypermethylation of promoter sequences associated with CpG islands and hypomethylation of CpG poor genes. Methylation levels of multiple CpG sites display a strong correlation to age common between individuals of the same species. Collectively, methylation of such CpG sites could be used as "epigenetic clocks" to predict biological age. Furthermore, the discrepancy between epigenetic and chronological ages could be predictive of all-cause mortality and multiple age-associated diseases. Random changes in DNA methylation (epigenetic drift) could also affect the aging phenotype, causing accidental changes in gene expression and increasing the transcriptional noise between cells of the same tissue. Both effects could become detrimental to tissue functioning and cause a gradual decline in organ function during aging. Strong evidence shows that epigenetic systems contribute to lifespan control in various organisms. Similar to other cell systems, the epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors. However, unlike mutations and many other hallmarks of aging, age-related epigenetic changes could be fully or partially reversed to a "young" state.


Assuntos
Envelhecimento , Epigênese Genética , Marcadores Genéticos , Envelhecimento/genética , Animais , Ilhas de CpG/genética , Metilação de DNA , Epigenômica , Marcadores Genéticos/genética , Longevidade
4.
Nat Commun ; 10(1): 3095, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300640

RESUMO

The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia (EPX, IL4, IL13) and genes previously associated with asthma and IgE in EWAS of blood (ACOT7, SLC25A25). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation.


Assuntos
Asma/diagnóstico , Metilação de DNA/imunologia , Inflamação/diagnóstico , Mucosa Nasal/imunologia , Adolescente , Asma/genética , Asma/imunologia , Asma/patologia , Biomarcadores/análise , Criança , Ilhas de CpG/genética , Ilhas de CpG/imunologia , Epigênese Genética/imunologia , Epigenômica/métodos , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Mucosa Nasal/patologia
5.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
6.
Biochim Biophys Acta Rev Cancer ; 1872(1): 74-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31201828

RESUMO

A prominent mucinous phenotype is observed in 10-15% of all colorectal cancers (CRCs). They are associated with a proximal location, and more commonly observed among tumors with mismatch repair defects and a promoter CpG methylator phenotype. However, none of these features has been clearly linked mechanistically to this mucinous subtype. Here, we propose that bacterial biofilms could represent a currently unappreciated contributor to mucinous CRC formation. The colonic microbiome and biofilms in particular, are emerging as important factors in tumor initiation and progression. Intriguingly, biofilms preferentially accompany proximal tumors, suggesting that there may be a direct mechanistic link with mucinous CRCs.


Assuntos
Adenocarcinoma Mucinoso/microbiologia , Biofilmes/crescimento & desenvolvimento , Biomarcadores Tumorais/genética , Neoplasias Colorretais/microbiologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA/genética , Humanos , Instabilidade de Microssatélites
7.
Nature ; 570(7759): 122-126, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092928

RESUMO

Transcriptional cofactors (COFs) communicate regulatory cues from enhancers to promoters and are central effectors of transcription activation and gene expression1. Although some COFs have been shown to prefer certain promoter types2-5 over others (for example, see refs 6,7), the extent to which different COFs display intrinsic specificities for distinct promoters is unclear. Here we use a high-throughput promoter-activity assay in Drosophila melanogaster S2 cells to screen 23 COFs for their ability to activate 72,000 candidate core promoters (CPs). We observe differential activation of CPs, indicating distinct regulatory preferences or 'compatibilities'8,9 between COFs and specific types of CPs. These functionally distinct CP types are differentially enriched for known sequence elements2,4, such as the TATA box, downstream promoter element (DPE) or TCT motif, and display distinct chromatin properties at endogenous loci. Notably, the CP types differ in their relative abundance of H3K4me3 and H3K4me1 marks (see also refs 10-12), suggesting that these histone modifications might distinguish trans-regulatory factors rather than promoter- versus enhancer-type cis-regulatory elements. We confirm the existence of distinct COF-CP compatibilities in two additional Drosophila cell lines and in human cells, for which we find COFs that prefer TATA-box or CpG-island promoters, respectively. Distinct compatibilities between COFs and promoters can explain how different enhancers specifically activate distinct sets of genes9, alternative promoters within the same genes, and distinct transcription start sites within the same promoter13. Thus, COF-promoter compatibilities may underlie distinct transcriptional programs in species as divergent as flies and humans.


Assuntos
Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Transcrição Genética , Ativação Transcricional , Animais , Linhagem Celular , Cromatina/genética , Ilhas de CpG/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Elementos Facilitadores Genéticos/genética , Histonas/metabolismo , Humanos , Especificidade por Substrato , TATA Box/genética , Sítio de Iniciação de Transcrição
8.
Nat Commun ; 10(1): 2246, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113950

RESUMO

Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer's disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Elementos Facilitadores Genéticos , Neurônios/patologia , Córtex Pré-Frontal/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Moléculas de Adesão Celular/genética , Disfunção Cognitiva/genética , Estudos de Coortes , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/citologia , Regulação para Cima
9.
Br J Surg ; 106(6): 682-691, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30945755

RESUMO

BACKGROUND: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer. METHODS: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis. RESULTS: Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1·46, 95 per cent c.i. 1·08 to 2·00, P = 0·014) and BRAF (OR 3·49, 2·50 to 4·87; P < 0·001) mutation, MSI (OR 3·98, 3·30 to 4·79; P < 0·001) and CIMP (OR 3·56, 2·85 to 4·43; P < 0·001), and negatively with altered p53 expression (OR 0·46, 0·31 to 0·67; P < 0·001). CONCLUSION: The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.


Assuntos
Adenocarcinoma Mucinoso/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma Mucinoso/patologia , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA , Humanos , Instabilidade de Microssatélites , Modelos Estatísticos , Mutação , Fenótipo , Antígeno Nuclear de Célula em Proliferação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
10.
BMC Genomics ; 20(1): 306, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014252

RESUMO

BACKGROUND: DNA methylation plays an important role in multiple biological processes that are closely related to human health. The study of DNA methylation can provide an insight into the mechanism behind human health and can also have a positive effect on the assessment of human health status. However, the available sequencing technology is limited by incomplete CpG coverage. Therefore, it is crucial to discover an efficient and convenient method capable of distinguishing between the states of CpG sites. Previous studies focused on identifying methylation states of the CpG sites in single cell, which only evaluated sequence information or structural information. RESULTS: In this paper, we propose a novel model, LightCpG, which combines the positional features with the sequence and structural features to provide information on the CpG sites at two stages. Next, we used the LightGBM model for training of the CpG site identification, and further utilized sample extraction and merged features to reduce the training time. Our results indicate that our method achieves outstanding performance in recognition of DNA methylation. The average AUC values of our method using the 25 human hepatocellular carcinoma cells (HCC) cell datasets and six human heptoplastoma-derived (HepG2) cell datasets were 0.9616 and 0.9213, respectively. Moreover, the average training times for our method on the HCC and HepG2 datasets were 8.3 and 5.06 s, respectively. Furthermore, the computational complexity of our model was much lower compared with other available methods that detect methylation states of the CpG sites. CONCLUSIONS: In summary, LightCpG is an accurate model for identifying the DNA methylation status of CpG sites in single cells. Furthermore, three types of feature extraction methods and two strategies used in LightCpG are helpful for other prediction problems.


Assuntos
Ilhas de CpG/genética , Análise de Célula Única , Sequenciamento Completo do Genoma , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia
11.
BMC Cancer ; 19(1): 328, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953488

RESUMO

BACKGROUND: Cancer cells evolve and constitute heterogeneous populations that fluctuate in space and time and are subjected to selection generating intratumor heterogeneity. This phenomenon is determined by the acquisition of genetic/epigenetic alterations and their selection over time which has clinical implications on drug resistance. METHODS: DNA extracted from different tumor cell populations (breast carcinomas, cancer cell lines and cellular clones) were analyzed by MS-MLPA. Methylation profiles were used to generate a heterogeneity index to quantify the magnitude of epigenetic heterogeneity in these populations. Cellular clones were obtained from single cells derived of MDA-MB 231 cancer cell lines applying serial limiting dilution method and morphology was analyzed by optical microscopy and flow cytometry. Clones characteristics were examined through cellular proliferation, migration capacity and apoptosis. Heterogeneity index was also calculated from beta values derived from methylation profiles of TCGA tumors. RESULTS: The study of methylation profiles of 23 fresh breast carcinomas revealed heterogeneous allele populations in these tumor pieces. With the purpose to measure the magnitude of epigenetic heterogeneity, we developed an heterogeneity index based on methylation information and observed that all tumors present their own heterogeneity level. Applying the index calculation in pure cancer cell populations such as cancer cell lines (MDA-MB 231, MCF-7, T47D, HeLa and K-562), we also observed epigenetic heterogeneity. In addition, we detected that clones obtained from the MDA-MB 231 cancer cell line generated their own new heterogeneity over time. Using TCGA tumors, we determined that the heterogeneity index correlated with prognostic and predictive factors like tumor size (p = 0.0088), number of affected axillary nodes (p = 0.007), estrogen receptor expression (p < 0.0001) and HER2 positivity (p = 0.0007). When we analyzed molecular subtypes we found that they presented different heterogeneity levels. Interestingly, we also observed that all mentioned tumor cell populations shared a similar Heterogeneity index (HI) mean. CONCLUSIONS: Our results show that each tumor presents a unique epigenetic heterogeneity level, which is associated with prognostic and predictive factors. We also observe that breast tumor subtypes differ in terms of epigenetic heterogeneity, which could serve as a new contribution to understand the different prognosis of these groups.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Metilação de DNA/genética , Epigênese Genética , Adulto , Apoptose/genética , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Regiões Promotoras Genéticas/genética
12.
Oncol Rep ; 41(6): 3488-3498, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002356

RESUMO

Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5­methyltetrahydrofolate­homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT­qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age­ and sex­matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI­TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low­risk group had a higher methylation rate of CpG_6 compared to the medium­risk group. However, the medium­risk group had a higher CpG_46.47 methylation rate compared to the low­risk group. The methylation rates of CpG_26 and CpG_46.47 in the high­risk group were higher than these rates in the low­risk group, while the CpG_42.23.44 methylation rate was lower in the high­risk group than in the low­risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL­H (high) group (≥50x109/l) were lower than these in the ALL­NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.


Assuntos
Metilação de DNA/genética , Ferredoxina-NADP Redutase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Adolescente , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas , Fatores de Risco
13.
Brain Tumor Pathol ; 36(2): 84-91, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937703

RESUMO

Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 (IDH1) and IDH2, and H3 histone family member 3A, which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.


Assuntos
Metilação de DNA/genética , Glioma/genética , Adulto , Neoplasias Encefálicas/genética , Ilhas de CpG/genética , Metilases de Modificação do DNA/genética , Epigênese Genética/genética , Glioblastoma/genética , Glioma/patologia , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Mutação , O(6)-Metilguanina-DNA Metiltransferase/genética , Prognóstico , Regiões Promotoras Genéticas/genética
14.
Cell Mol Biol (Noisy-le-grand) ; 65(3): 94-100, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30942161

RESUMO

The purpose of this study was to investigate the difference of Twist gene promoter methylation among ovarian ectopic endometrium, eutopic endometrium and non-endometriosis (EMs) endometrium . 15 patients with reproductive age hospitalized at Department of obstetrics and gynecology affiliated to Medicine School of Zhejiang University from January 2013 to June 2016 were selected. Among them, 5 patients underwent laparoscopic surgery due to ovarian type EMs, and were selected after histologic confirmation. Ectopic endometrium and eutopic endometrium were obtained simultaneously. Normal endometrium was obtained from 5 cases of tubal infertility confirmed by hysteroscopy. Six pairs of primers for CpG island of Twist gene promoter were designed, and the difference of promoter methylation levels was detected by pyrosequencing method for methylation specific PCR (MSP) in three groups of endometrial tissues. The promoter of Twist gene is hypomethylated in some areas of ovarian ectopic endometrium and eutopic endometrium of ovarian endometriosis. It is speculated that the regional hypomethylation of Twist gene promoter in ovarian ectopic endometrium and eutopic endometrium may cause over-expression of Twist protein, which may directly lead to the pathogenesis of endometriosis.


Assuntos
Metilação de DNA/genética , Endometriose/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Adulto , Ilhas de CpG/genética , Endométrio/metabolismo , Endométrio/patologia , Feminino , Regulação da Expressão Gênica , Loci Gênicos , Humanos , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Células Estromais/metabolismo , Células Estromais/patologia , Proteína 1 Relacionada a Twist/metabolismo
15.
BMC Bioinformatics ; 20(Suppl 4): 119, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999858

RESUMO

BACKGROUND: The search for molecular biomarkers of early-onset colorectal cancer (CRC) is an important but still quite challenging and unsolved task. Detection of CpG methylation in human DNA obtained from blood or stool has been proposed as a promising approach to a noninvasive early diagnosis of CRC. Thousands of abnormally methylated CpG positions in CRC genomes are often located in non-coding parts of genes. Novel bioinformatic methods are thus urgently needed for multi-omics data analysis to reveal causative biomarkers with a potential driver role in early stages of cancer. METHODS: We have developed a method for finding potential causal relationships between epigenetic changes (DNA methylations) in gene regulatory regions that affect transcription factor binding sites (TFBS) and gene expression changes. This method also considers the topology of the involved signal transduction pathways and searches for positive feedback loops that may cause the carcinogenic aberrations in gene expression. We call this method "Walking pathways", since it searches for potential rewiring mechanisms in cancer pathways due to dynamic changes in the DNA methylation status of important gene regulatory regions ("epigenomic walking"). RESULTS: In this paper, we analysed an extensive collection of full genome gene-expression data (RNA-seq) and DNA methylation data of genomic CpG islands (using Illumina methylation arrays) generated from a sample of tumor and normal gut epithelial tissues of 300 patients with colorectal cancer (at different stages of the disease) (data generated in the EU-supported SysCol project). Identification of potential epigenetic biomarkers of DNA methylation was performed using the fully automatic multi-omics analysis web service "My Genome Enhancer" (MGE) (my-genome-enhancer.com). MGE uses the database on gene regulation TRANSFAC®, the signal transduction pathways database TRANSPATH®, and software that employs AI (artificial intelligence) methods for the analysis of cancer-specific enhancers. CONCLUSIONS: The identified biomarkers underwent experimental testing on an independent set of blood samples from patients with colorectal cancer. As a result, using advanced methods of statistics and machine learning, a minimum set of 6 biomarkers was selected, which together achieve the best cancer detection potential. The markers include hypermethylated positions in regulatory regions of the following genes: CALCA, ENO1, MYC, PDX1, TCF7, ZNF43.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , Retroalimentação Fisiológica , Transdução de Sinais/genética , Sítios de Ligação/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Transcrição/metabolismo
16.
Cancer Causes Control ; 30(6): 637-649, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963391

RESUMO

BACKGROUND: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.


Assuntos
Cálcio/administração & dosagem , Neoplasias do Colo/patologia , Ilhas de CpG/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Neoplasias do Colo/genética , Metilação de DNA , Feminino , Seguimentos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Fenótipo , Modelos de Riscos Proporcionais , Risco
17.
Biomed Pharmacother ; 113: 108655, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849637

RESUMO

In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/biossíntese , Neoplasias Esofágicas/metabolismo , Éxons/genética , RNA Longo não Codificante/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Ilhas de CpG/genética , Epigênese Genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Modelos Lineares , Masculino , Prognóstico , RNA Longo não Codificante/genética , Análise de Sobrevida , Proteínas Supressoras de Tumor/genética , Regulação para Cima
18.
Int Immunopharmacol ; 70: 467-476, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861467

RESUMO

CpG oligodeoxynucleotides (CpG-ODN) is an immunoenhancer, which is composed of unmethylated cytosine and guanine. Host Defense Peptides (HDPs) are small molecule polypeptides with various immunological activities that have been shown to induce a stronger innate immune response in piglets with synthetic CpG-ODN. Therefore, combination of CpG-ODN and HDPs was expected to be a novel immunoadjuvant with high efficiency, low toxicity and great potential. However, cost of synthetic HDPs or CpG-ODN is too high to be advantageous for animal farming. In this study, in order to improve the immune function of vaccine and reduce cost, a series of recombinant plasmids (containing HDPs gene (PR-39/pBD-1) and different numbers of CpG motifs) were constructed. In vitro, porcine lymphocytes were stimulated by recombinant plasmids to verify the immunostimulatory function of recombinant plasmids. In vivo, recombinant plasmids were used to immunize piglets with Enterotoxigenic Escherichia coli (ETEC) vaccine to analyze effects of recombinant plasmids on the mucosal immune responses. In addition, dosage screening and capability of maternal antibody responses were also investigated. Our results showed that recombinant plasmids had strong adjuvant effects especially the plasmid pVAX49-PR-39 and pVAX49-pBD-1. Moreover, there was no diarrhea in piglets using pVAX49-PR-39 or pVAX49-pBD-1 as adjuvants. These findings suggested that recombinant plasmids (containing PR-39/pBD-1 and CpG) as adjuvants of vaccines could enhance immune stimulation better than HDPs or CpG alone. It has a good protective effect on maintaining health of newborn piglets. Among them, both plasmids pVAX49-PR-39 and pVAX49-pBD-1 could be used as effective vaccine adjuvants for piglets.


Assuntos
Vacinas Bacterianas/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/fisiologia , Intestinos/imunologia , Suínos/imunologia , Imunidade Adaptativa , Adjuvantes Imunológicos/genética , Agricultura , Animais , Animais Recém-Nascidos , Peptídeos Catiônicos Antimicrobianos/genética , Vacinas Bacterianas/genética , Ilhas de CpG/genética , DNA Recombinante/genética , Feminino , Imunidade Humoral , Imunidade Inata , Imunidade Materno-Adquirida , Imunização , Plasmídeos/genética , Gravidez
19.
Gene ; 699: 80-87, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30858137

RESUMO

Transcriptional regulation is impacted by the organization of the genome into chromatin compartments and domains. We previously reported the application of a biochemical fractionation protocol to isolate highly enriched transcribed DNA from chicken polychromatic erythrocytes. In conjunction with next-generation DNA and RNA sequencing as well as chromatin immunoprecipitation-DNA sequencing, we identified all the active chromosomal compartments and determined their structural signatures in relation to expression levels. Highly expressed genes were found in broad dynamically highly acetylated, salt-soluble chromatin compartments, while poorly or moderately expressed genes exhibited a narrow stretch of salt-soluble chromatin limited to their 5' or body region. Here, we present the detailed characteristics, including the location of nucleosome-free regions and CpG islands, of several transcriptionally active chromatin compartments. These chromatin patterns illustrate how the salt solubility profile of a genomic region aids in the annotation of genes expressed in erythroid cells and contributes to the identification of functional features such as regulatory regions.


Assuntos
Galinhas/genética , Cromatina/genética , Eritrócitos/fisiologia , Transcrição Genética/genética , Acetilação , Animais , Ilhas de CpG/genética , DNA/genética , Regulação da Expressão Gênica/genética , Nucleossomos/genética
20.
Nat Commun ; 10(1): 1209, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872577

RESUMO

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.


Assuntos
Doenças Cardiovasculares/genética , Ilhas de CpG/genética , Epigênese Genética , Doenças Metabólicas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tecido Adiposo/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Metilação de DNA , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lipídeos/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
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