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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.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 769-772, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400124

RESUMO

OBJECTIVE: To explore the characteristics of differentially methylated genes and gene ontology associated with neural tube defects (NTDs). METHODS: Twelve subjects from 3 NTDs pedigrees were enrolled. Patients with NTDs have served as the case group, while their family members with normal phenotypes have served as the control group. Genomic DNA was extracted from peripheral venous blood samples of the families and used for DNA methylation analysis. Pairwise comparison was carried out primarily for patient-offspring pairs, and co-segregation of methylation pattern with NTDs was analyzed. Pathway related to differentially methylated genes was predicted with DAVID software. RESULTS: Pairwise comparison indicated that VTRNA2-1 was the only gene in which all CpG sites were methylated. Co-segregation of VTRNA2-1 gene methylation with NTDs was found in all pedigrees. Pathways of hypermethylated genes included plasma membrane component, regulation of cellular protein metabolic process, and regulation of actin cytoskeleton organization, while the pathways of hypomethylated genes have included transcription regulator activity, cell adhesion, and neuronal differentiation. CONCLUSION: Methylation of the VTRNA2-1 gene has co-segregated with NTDs in the studied pedigrees. The pathways of differentially methylated genes has involved with mechanism of neural tube development.


Assuntos
Metilação de DNA , MicroRNAs/genética , Defeitos do Tubo Neural/genética , Ilhas de CpG , Ontologia Genética , Humanos , Linhagem
5.
Medicine (Baltimore) ; 98(28): e16424, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305461

RESUMO

Although the changes in DNA methylation are assumed to be due to the association between adverse intrauterine conditions and adult metabolic health, evidence from human studies is rare. Little is known about the changes in DNA methylation present at birth that affect metabolic profiles in childhood. Previous studies have shown that the melanocortin 4 receptor (MC4R) and hepatocyte nuclear factor 4 alpha (HNF4α) genes are associated with obesity and metabolic disorders. Thus, we investigated the associations of the DNA methylation statuses of MC4R and HNF4α in cord blood with metabolic profiles in childhood.We collected data from 90 children 7 to 9 years of age included in the Ewha Birth & Growth Cohort Study in Korea. DNA methylation was analyzed by pyrosequencing. The children were split into 2 groups according to the cutoff triglyceride (TG) levels (<110 and ≥110 mg/dL).The methylation statuses of MC4R and HNF4α at birth were significantly associated with the TG level in childhood (P < .05). It was interesting to note that the methylation statuses of MC4R and HNF4α in cord blood were significantly decreased, whereas childhood body mass index was significantly increased, in children with high TG levels compared with children with low TG levels (P < .05).Our findings show that the methylation statuses of MC4R and HNF4α at birth are associated with metabolic profiles in childhood. These epigenetic modifications occurring in early life may contribute to subsequent metabolic-related disorders. Thus, we suggest that DNA methylation status in cord blood may be predictive of the risk of developing metabolic syndrome.


Assuntos
Metilação de DNA , Fator 4 Nuclear de Hepatócito/genética , Regiões Promotoras Genéticas , Receptor Tipo 4 de Melanocortina/genética , Triglicerídeos/sangue , Índice de Massa Corporal , Criança , Desenvolvimento Infantil , Ilhas de CpG , Epigênese Genética , Feminino , Sangue Fetal/metabolismo , Seguimentos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Receptor Tipo 4 de Melanocortina/metabolismo
6.
Gene ; 712: 143954, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31288058

RESUMO

BACKGROUND: Breast cancer (BC) is the highest cause of mortality among female cancer patients. In some cases, BC is due to Poly [ADP-ribose] polymerase 1 (PARP1) gene dysregulation, which has been involved in various important cellular processes. Among Iranian women, the association between PARP1 polymorphisms and BC was never studied before so in this case-control study, the genetic association of three SNPs (rs1136410, rs907187 and rs4653734) was analyzed with susceptibility to BC. METHODS: The study subjects were 386 Iranian females divided into 186 patients and 200 healthy controls. The genotypes of PARP1 variants were detected using ARMS and a combined ARMS-RFLP PCR method. RESULTS: The results showed that Carriers of CG and GG genotypes of the variant rs4653734 were at higher risk of BC compared with wild-type carriers (CC) and this variant was statistically significant under a recessive model of inheritance. Moreover, rs907187 was related to increased BC risk in the CC and GG genotypes under dominant and recessive models of inheritance. The G allele frequency of rs4653734 and rs907187 was higher in breast cancer patients than in normal subjects. No association was detected between rs1136410 and susceptibility to BC among studied groups. Furthermore, A-G-C haplotype was linked to an increased BC risk, whereas A-C-C and A-C-G haplotypes were related to a decreased risk of BC. In Silico predictions suggested that rs907187 affects E2F and E2F-4 transcription factors binding site. CONCLUSIONS: The current study suggests that rs907187 and rs4653734 have remarkable associations with BC risk among Iranian women.


Assuntos
Neoplasias da Mama/genética , Desequilíbrio de Ligação , Poli(ADP-Ribose) Polimerase-1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Ilhas de CpG , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Irã (Geográfico)/epidemiologia , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Fatores de Transcrição/metabolismo
7.
Nat Commun ; 10(1): 2461, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165727

RESUMO

Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.


Assuntos
Citosina/metabolismo , Metilação de DNA , Nefropatias Diabéticas/genética , Rim/metabolismo , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Epigênese Genética , Feminino , Fibrose , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade
8.
Cytogenet Genome Res ; 158(2): 56-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158835

RESUMO

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.


Assuntos
Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos do Crescimento/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Condrócitos , Ilhas de CpG , Variações do Número de Cópias de DNA , Feminino , Humanos , Análise de Sequência de DNA
9.
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
10.
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
11.
BMC Bioinformatics ; 20(1): 218, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035919

RESUMO

BACKGROUND: When designing an epigenome-wide association study (EWAS) to investigate the relationship between DNA methylation (DNAm) and some exposure(s) or phenotype(s), it is critically important to assess the sample size needed to detect a hypothesized difference with adequate statistical power. However, the complex and nuanced nature of DNAm data makes direct assessment of statistical power challenging. To circumvent these challenges and to address the outstanding need for a user-friendly interface for EWAS power evaluation, we have developed pwrEWAS. RESULTS: The current implementation of pwrEWAS accommodates power estimation for two-group comparisons of DNAm (e.g. case vs control, exposed vs non-exposed, etc.), where methylation assessment is carried out using the Illumina Human Methylation BeadChip technology. Power is calculated using a semi-parametric simulation-based approach in which DNAm data is randomly generated from beta-distributions using CpG-specific means and variances estimated from one of several different existing DNAm data sets, chosen to cover the most common tissue-types used in EWAS. In addition to specifying the tissue type to be used for DNAm profiling, users are required to specify the sample size, number of differentially methylated CpGs, effect size(s) (Δß), target false discovery rate (FDR) and the number of simulated data sets, and have the option of selecting from several different statistical methods to perform differential methylation analyses. pwrEWAS reports the marginal power, marginal type I error rate, marginal FDR, and false discovery cost (FDC). Here, we demonstrate how pwrEWAS can be applied in practice using a hypothetical EWAS. In addition, we report its computational efficiency across a variety of user settings. CONCLUSION: Both under- and overpowered studies unnecessarily deplete resources and even risk failure of a study. With pwrEWAS, we provide a user-friendly tool to help researchers circumvent these risks and to assist in the design and planning of EWAS. AVAILABILITY: The web interface is written in the R statistical programming language using Shiny (RStudio Inc., 2016) and is available at https://biostats-shinyr.kumc.edu/pwrEWAS/ . The R package for pwrEWAS is publicly available at GitHub ( https://github.com/stefangraw/pwrEWAS ).


Assuntos
Epigênese Genética , Interface Usuário-Computador , Ilhas de CpG , Metilação de DNA , Humanos , Modelos Lineares , Fenótipo , Modelos de Riscos Proporcionais , Vaping
12.
Toxicol Lett ; 311: 98-104, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063829

RESUMO

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD) exposure during embryonic gonadal sex determination had been demonstrated to harm the ovarian development. However, its mechanism was unclear and possibly related to epigenetic regulation. In the present study, the pregnant rats were treated with TCDD (100 ng/kg/day or 500 ng/kg/day) or only vehicle and corn oil on the day 8-14 of gestation through the gavage with a stainless-steel feeding needle. The vaginal opening time and estrous cycle of female offspring rats (F1) were monitored twice a day. The ovarian histology, follicle count, real-time PCR, Western Blotting and DNA methylation analysis for Igf2 and H19 were carried out. The results showed that maternal TCDD exposure disrupted estrous cyclicity, resulted in aberrant concentration of serum E2 and FSH, and affected the number of primordial follicles, secondary follicles and corpus luteum. However, TCDD had no effect on the number of primary follicles and atresia follicles. Furthermore, the mRAN expression of imprinted genes Igf2 and H19 was down-regulated, and the IGF2 protein was also down-regulated. TCDD exposure did not alter the mean methylation rate of Igf2 DMR2 and H19 ICR, and only some CpG sites throughout them were hypermethylated in high-dose TCDD rats. In conclusion, maternal exposure of TCDD could affect the ovary development and functions which were possibly associated with down-regulation expression of IGF2 and H19. However, it was not entirely clear whether the impairment of ovary by TCDD was related to the methylation pattern of Igf2 and H19 ICR.


Assuntos
Epigênese Genética/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/genética , Doenças Ovarianas/induzido quimicamente , Ovário/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , RNA Longo não Codificante/genética , Animais , Ilhas de CpG/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estradiol/sangue , Ciclo Estral/sangue , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/genética , Feminino , Hormônio Foliculoestimulante/sangue , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Impressão Genômica/efeitos dos fármacos , Idade Gestacional , Fator de Crescimento Insulin-Like II/metabolismo , Exposição Materna , Doenças Ovarianas/genética , Doenças Ovarianas/metabolismo , Doenças Ovarianas/patologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Ovário/metabolismo , Ovário/patologia , Gravidez , RNA Longo não Codificante/metabolismo , Ratos , Ratos Sprague-Dawley
13.
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
14.
Poult Sci ; 98(8): 3257-3267, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31064004

RESUMO

Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase that adds TTAGGG repeats to the 3'-overhang of telomeres. In the present study, we detected that the duck TERT (dTERT) gene was highly expressed in small intestine and kidney, followed by heart, leg muscle, spleen, pancreas, gonad, and liver at neonatal stage. From embryonic to neonatal stage, the highest dTERT mRNA in liver appeared at stage E19 (19 days at embryonic stage), while for the leg muscle the maximum expression occurred at E26. We also measured the relative telomerase activity (RTA) and relative telomere length (RTL) in the examined tissues and found that the changed tendency of RTA and RTL was not very consistent with that of TERT. In silico analysis revealed that there were three CpG islands (S1, S2, and S3) within the 5' regulatory region of the dTERT gene. Bisulfite sequencing PCR (BSP) assay showed that liver (D7, 7 days after birth) which expressed significantly lower dTERT mRNA had an obviously higher methylation level of S1 compared with small intestine (D7) or liver (E19). Quantitative real-time PCR analysis revealed that the expression of DNA methyltransferase DNMT1 in liver (D7) was significantly higher than that in small intestine (D7) or in liver (E19). In vitro, dTERT expression was upregulated and the methylation status of S1 decreased in both duck embryonic fibroblasts and small intestinal epithelial cells following treatment with the demethylation reagent, 5-aza-2'-deoxycytidine (5-aza-dC), further suggesting that dTERT is epigenetically regulated by DNA methylation. This work lays a solid foundation for further study of TERT function and regulation in avian species.


Assuntos
Metilação de DNA , Patos/genética , Regulação da Expressão Gênica no Desenvolvimento , Telomerase/genética , Animais , Células Cultivadas , Simulação por Computador , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Decitabina/farmacologia , Patos/crescimento & desenvolvimento , Patos/metabolismo , Embrião não Mamífero , Telômero
15.
Mol Med Rep ; 19(6): 4631-4636, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059029

RESUMO

Immediate­early response gene 5 (IER5) is a gene involved in the regulation of the cell cycle, and its structure and function have been investigated by bioinformatics analyses. The present study determined the sites of promoter methylation and gene ontology (GO) annotations associated with IER5. In addition, we conducted a prediction analysis to determine the physical and chemical properties, hydrophobicity/hydrophilicity, posttranslational modification, subcellular localization, transmembrane structure, signal peptide and secondary and tertiary structures of IER5. One CpG island and several methylated sites were identified close to the promoter of IER5. The GO analysis suggested that IER5 could bind ions and proteins that were mainly associated with metabolic processes. IER5 comprised 327 amino acids and was reported to be an unstable hydrophilic protein with an isoelectric point of 4.91. A total of 18 O­glycosylation sites and 22 phosphorylation sites were identified within this protein. The subcellular localization of IER5 was mainly in the nucleus, and its main secondary structural element was the α­helix. Bioinformatic analyses of the features of IER5 may improve understanding of its structure and function; however, experimental verification is required.


Assuntos
Biologia Computacional , Proteínas Imediatamente Precoces/genética , Proteínas Nucleares/genética , Sequência de Aminoácidos , Ciclo Celular/genética , Ilhas de CpG , Proteínas de Ligação a DNA , Ontologia Genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Regiões Promotoras Genéticas , Conformação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição , Transcrição Genética
16.
Nat Commun ; 10(1): 2146, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086175

RESUMO

Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.


Assuntos
Neoplasias Encefálicas/genética , Ependimoma/genética , Glioma/genética , Proteínas Oncogênicas/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Animais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Ilhas de CpG , Fossa Craniana Posterior , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Ependimoma/patologia , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Células HEK293 , Histonas , Humanos , Camundongos , Proteínas Oncogênicas/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
17.
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
18.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035542

RESUMO

The etiology of cerebral palsy (CP) is complex and remains inadequately understood. Early detection of CP is an important clinical objective as this improves long term outcomes. We performed genome-wide DNA methylation analysis to identify epigenomic predictors of CP in newborns and to investigate disease pathogenesis. Methylation analysis of newborn blood DNA using an Illumina HumanMethylation450K array was performed in 23 CP cases and 21 unaffected controls. There were 230 significantly differentially-methylated CpG loci in 258 genes. Each locus had at least 2.0-fold change in methylation in CP versus controls with a FDR p-value ≤ 0.05. Methylation level for each CpG locus had an area under the receiver operating curve (AUC) ≥ 0.75 for CP detection. Using Artificial Intelligence (AI) platforms/Machine Learning (ML) analysis, CpG methylation levels in a combination of 230 significantly differentially-methylated CpG loci in 258 genes had a 95% sensitivity and 94.4% specificity for newborn prediction of CP. Using pathway analysis, multiple canonical pathways plausibly linked to neuronal function were over-represented. Altered biological processes and functions included: neuromotor damage, malformation of major brain structures, brain growth, neuroprotection, neuronal development and de-differentiation, and cranial sensory neuron development. In conclusion, blood leucocyte epigenetic changes analyzed using AI/ML techniques appeared to accurately predict CP and provided plausible mechanistic information on CP pathogenesis.


Assuntos
Inteligência Artificial , Ácidos Nucleicos Livres , Paralisia Cerebral/genética , Aprendizado Profundo , Epigênese Genética , Estudos de Casos e Controles , Paralisia Cerebral/sangue , Paralisia Cerebral/metabolismo , Ilhas de CpG , Metilação de DNA , Epigenômica/métodos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Recém-Nascido , Curva ROC
19.
BMC Genomics ; 20(1): 324, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035926

RESUMO

BACKGROUND: During decidualization in endometrial stromal cells (ESCs), expressions of a number of genes and epigenetic modifications of histones are altered. However, there is little information about whether DNA methylation, which is another epigenetic mechanism, also changes during decidualization. Here, we examined the genome-wide DNA methylation profiles in ESCs during decidualization and their associations with the changes of gene expressions and histone modifications. RESULTS: ESCs were incubated with estradiol and medroxyprogesterone acetate for 14 days to induce decidualization. The genome-wide DNA methylation profiles were compared between the non-decidualized ESCs and the decidualized ESCs. Of 482,005 CpGs, only 23 CpGs (0.0048%) showed different DNA methylation statuses. The DNA methylation statuses of the differentially expressed genes and the regions with different histone modifications (H3K4 tri-methylation and H3K27 acetylation) were also compared between the ESCs. In the upregulated and downregulated genes in decidualized ESCs, DNA methylation statuses around the promoter region of the genes did not significantly differ between the ESCs. In the regions with different histone modification, DNA methylation statuses did not differ between the ESCs. The differentially expressed genes and the differential histone modification regions were hypomethylated. CONCLUSIONS: Culturing ESCs with estrogen/progesterone did not distort the physiological pattern of DNA methylation, although mRNA expression and histone modifications were dynamically altered. A genome-wide DNA methylation analysis revealed stable DNA methylation statuses during decidualization in human endometrial stromal cells. DNA hypomethylation is maintained for the variable changes of histone modifications and gene expression during decidualization.


Assuntos
Metilação de DNA , Genoma Humano , Células Cultivadas , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Endométrio/citologia , Estradiol/farmacologia , Feminino , Histonas/metabolismo , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Acetato de Medroxiprogesterona/farmacologia , Células Estromais/citologia , Células Estromais/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Gene ; 707: 58-64, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31075408

RESUMO

We investigated the activity of chondrogenic markers and variation of methylation patterns in equine cartilaginous cells cultivated in monolayer. The transcriptional and epigenetic effect of the long-term culture of chondrocytes has been evaluated using several passages of chondrocyte cell-lines derived from equine articular cartilage. Using 3 genes as endogenous control we tested the expression of 7 genes important for different stages of chondrocyte differentiation and maturation. CpG islands in RUNX3 locus were inspected for the evaluation of differential methylation state of passaged cell-lines. The general decline of transcript abundance of marker loci was detected in passage 11 which is the sign of dedifferentiation of cultivated chondrocytes in prolonged monolayer culture. Passages 13 and 14 were characterized by the upregulation of a number of genes, possibly due to the heterogeneity of developed cell lines at this stage of the culture. Instead, gradual increase of methylation percent at particular CpG sites of RUNX3 locus was associated with the growing number of passage. This finding led us to the conclusion that epigenetic alterations better describe the stage of cultivated chondrocytes.


Assuntos
Técnicas de Cultura de Células/métodos , Condrócitos/citologia , Condrogênese , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Metilação de DNA , Perfilação da Expressão Gênica/veterinária , Animais , Técnicas de Cultura de Células/veterinária , Diferenciação Celular , Linhagem Celular , Condrócitos/metabolismo , Ilhas de CpG , Epigênese Genética , Regulação da Expressão Gênica , Cavalos
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