The etiology of Autism Spectrum Disorders (ASD) is a result of the interaction between genes and the environment. The study of epigenetic factors that affect gene expression, such as DNA methylation, ...has become an important area of research in ASD. In recent years, there has been an increasing body of evidence pointing to epigenetic mechanisms that influence brain development, as in the case of ASD, when gene methylation dysregulation is present. Our analysis revealed 853 differentially methylated CpG in ASD patients, affecting 509 genes across the genome. Enrichment analysis showed five related diseases, including autistic disorder and mental disorders, which are particularly significant. In this work, we identified 64 genes that were previously reported in the SFARI gene database, classified according to their impact index. Additionally, we identified new genes that have not been previously reported as candidates with differences in the methylation patterns of Mexican children with ASD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Leukemia is a neoplasm with high incidence and mortality rates. Mitotic death has been observed in tumor cells treated with chemotherapeutic agents. Ras family proteins participate in the ...transduction of signals involved in different processes, such as proliferation, differentiation, survival, and paradoxically, initiation of cell death.
This study investigated the effect of
expression on human T-cell acute lymphoblastic leukemia MOLT-4 cells. Cells were electroporated with either wild-type (Ras
) or oncogenic mutant in codon 12 exon 1 (Ras
) versions of
gene and stained for morphological analysis. Cell viability was assessed using trypan blue staining and cell cycle analysis using flow cytometry.
gene expression was determined using quantitative real-time reverse transcription polymerase chain reaction. The
, ANOVA, and Scheffe tests were used for statistical analysis.
Human T-cell acute lymphoblastic leukemia MOLT-4 cells showed nuclear fragmentation and presence of multiple nuclei and micronuclei after transfection with either wt or mutant
genes. Cell cycle analysis revealed a statistically significant increase in cells in the S phase when transfected with either wt (83.67%,
<0.0005) or mutated (81.79%,
<0.0001)
genes. Although similar effects for both versions of
were found, cells transfected with the mutated version died at 120 h of mitotic catastrophe.
Transfection of human T-cell acute lymphoblastic leukemia MOLT-4 cells with either normal or mutated
genes induced alterations in morphology, arrest in the S phase, and death by mitotic catastrophe.
Obesity is accompanied by excess adipose fat storage, which may lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Currently, the tendency to develop T2D in obesity cannot be ...explained by genetic variation alone-epigenetic mechanisms, such as DNA methylation, might be involved. Here, we aimed to identify changes in DNA methylation and gene expression in visceral adipose tissue (VAT) that might underlie T2D susceptibility in patients with obesity.
We investigated DNA methylation and gene expression in VAT biopsies from 19 women with obesity, without (OND = 9) or with T2D (OD = 10). Differences in genome-scale methylation (differentially methylated CpGs DMCs, false discovery rate < 0.05; and differentially methylated regions DMRs, p value < 0.05) and gene expression (DEGs, p value <0.05) between groups were assessed. We searched for overlap between altered methylation and expression and the impact of altered DNA methylation on gene expression, using bootstrap Pearson correlation. The relationship of altered DNA methylation to T2D-related traits was also tested.
We identified 11 120 DMCs and 96 DMRs distributed across all chromosomes, with the greatest density of epigenomic alterations at the MHC locus. These alterations were found in newly and previously T2D-related genes. Several of these findings were supported by validation and extended multi-ethnic analyses. Of 252 DEGs in the OD group, 68 genes contained DMCs (n = 88), of which 24 demonstrated a significant relationship between gene expression and methylation (p values <0.05). Of these, 16, including ATP11A, LPL and EHD2 also showed a significant correlation with fasting glucose and HbA1c levels.
Our results revealed novel candidate genes related to T2D pathogenesis in obesity. These genes show perturbations in DNA methylation and expression profiles in patients with obesity and diabetes. Methylation profiles were able to discriminate OND from OD individuals; DNA methylation is thus a potential biomarker.
Obesity is a well-recognized risk factor for insulin resistance and type 2 diabetes (T2D), although the precise mechanisms underlying the relationship remain unknown. In this study we identified ...alterations of DNA methylation influencing T2D pathogenesis, in subcutaneous and visceral adipose tissues, liver, and blood from individuals with obesity.
The study included individuals with obesity, with and without T2D. From these patients, we obtained samples of liver tissue (n = 16), visceral and subcutaneous adipose tissues (n = 30), and peripheral blood (n = 38). We analyzed DNA methylation using Illumina Infinium Human Methylation arrays, and gene expression profiles using HumanHT-12 Expression BeadChip Arrays.
Analysis of DNA methylation profiles revealed several loci with differential methylation between individuals with and without T2D, in all tissues. Aberrant DNA methylation was mainly found in the liver and visceral adipose tissue. Gene ontology analysis of genes with altered DNA methylation revealed enriched terms related to glucose metabolism, lipid metabolism, cell cycle regulation, and response to wounding. An inverse correlation between altered methylation and gene expression in the four tissues was found in a subset of genes, which were related to insulin resistance, adipogenesis, fat storage, and inflammation.
Our present findings provide additional evidence that aberrant DNA methylation may be a relevant mechanism involved in T2D pathogenesis among individuals with obesity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute myeloid leukemia is characterized by its high biological and clinical heterogeneity, which represents an important barrier for a precise disease classification and accurate therapy. While ...epigenetic aberrations play a pivotal role in acute myeloid leukemia pathophysiology, molecular signatures such as change in the DNA methylation patterns and genetic mutations in enzymes needed to the methylation process can also be helpful for classifying acute myeloid leukemia. Our study aims to unveil the relevance of DNMT3A and TET2 genes in global and specific methylation patterns in acute myeloid leukemia. Peripheral blood samples from 110 untreated patients with acute myeloid leukemia and 15 healthy control individuals were collected. Global 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from peripheral blood leukocytes were measured by using the MethylFlashTM Quantification kits. DNMT3A and TET2 expression levels were evaluated by real-time quantitative polymerase chain reaction. The R882A hotspot of DNMT3A and exons 6–10 of TET2 were amplified by polymerase chain reaction and sequenced using the Sanger method. Methylation patterns of 16 gene promoters were evaluated by pyrosequencing after treating DNA with sodium bisulfite, and their transcriptional products were measured by real-time quantitative polymerase chain reaction.Here, we demonstrate altered levels of 5-methylcytosine and 5-hydroxymethylcytosine and highly variable transcript levels of DNMT3A and TET2 in peripheral blood leukocytes from acute myeloid leukemia patients. We found a mutation prevalence of 2.7% for DNMT3A and 11.8% for TET2 in the Mexican population with this disease. The average overall survival of acute myeloid leukemia patients with DNMT3A mutations was only 4 months. In addition, we showed that mutations in DNMT3A and TET2 may cause irregular DNA methylation patterns and transcriptional expression levels in 16 genes known to be involved in acute myeloid leukemia pathogenesis. Our findings suggest that alterations in DNMT3A and TET2 may be associated with acute myeloid leukemia prognosis. Furthermore, alterations in these enzymes affect normal methylation patterns in acute myeloid leukemia– specific genes, which in turn, may influence patient survival.
Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the ...most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.L125F, a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.
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•Frequency of L125F MATE1 variant in Mexican population suggests an Amerindian origin.•This is the first pharmacogenetic study in a L125F homozygous individual.•L125F MATE1 has an additive effect on metformin plasma accumulation.•The L125F homozygous patient showed hyperlactatemia after metformin administration.•Molecular dynamics showed that L125F reduces the permeability of the transporter.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The function of dystrophin Dp71 in neuronal cells remains to be established. Previously, we revealed the involvement of this protein in both nerve growth factor (NGF)-induced neuronal differentiation ...and cell adhesion by isolation and characterization of PC12 neuronal cells with depleted levels of Dp71. In this work, a novel phenotype of Dp71-knockdown cells was characterized, which is their delayed growth rate. Cell cycle analyses revealed an altered behavior of Dp71-depleted cells, which consists of a delay in G0/G1 transition and an increase in apoptosis during nocodazole-induced mitotic arrest. Dp71 associates with lamin B1 and β-dystroglycan, proteins involved in aspects of the cell division cycle; therefore, we compared the distribution of Dp71 with that of lamin B1 and β-dystroglycan in PC12 cells at mitosis and cytokinesis by means of immunofluorescence and confocal microscopy analysis. All of these three proteins exhibited a similar immunostaining pattern, localized at mitotic spindle, cleavage furrow, and midbody. It is noteworthy that a drastic decreased staining in mitotic spindle, cleavage furrow, and midbody was observed for both lamin B1 and β-dystroglycan in Dp71-depleted cells. Furthermore, we demonstrated the interaction of Dp71 with lamin B1 in PC12 cells by immunoprecipitation and pull-down assays, and importantly, we revealed that knockdown of Dp71 expression caused a marked reduction in lamin B1 levels and altered localization of the nuclear envelope protein emerin. Our data indicate that Dp71 is a component of the mitotic spindle and cytokinesis multi-protein apparatuses that might modulate the cell division cycle by affecting lamin B1 and β-dystroglycan levels.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: Our objective was to evaluate the frequency of expression and determine the expression levels of the NY-ESO-1 gene in patients with DLBCL as well as to examine its relationship with ...clinical parameters and survival. Methods: We analyzed NY-ESO-1 gene expression levels using real-time quantitative RT-PCR (RT-qPCR) in 112 patients with DLBCL. The associations between the expression of the NY-ESO-1 gene and the clinical variables were evaluated using the Chi-square test and Fisher’s exact test. Overall survival (OS) was determined using the Kaplan–Meier method. Result: The results showed that the NY-ESO-1 gene was expressed in 46.4% (52/112) of patients with DLBCL, and NY-ESO-1 gene expression was associated with clinical parameters such as LDH, clinical stage, and International Prognostic Index (IPI) (p ≤ 0.05). High levels of NY-ESO-1 gene expression were associated with advanced disease stages, and the survival rates after 5.3 years of tracking were lower in the patients expressing the NY-ESO-1 gene (66.4%) than in those not expressing the gene (23.1%). Conclusion: The expression levels of the NY-ESO-1 gene in patients with DLBCL may be of great utility for diagnosing and determining the prognosis of this disease.
Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American ...populations have been underrepresented in these studies.
To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia.
We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r
threshold of 0.1.
Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the
gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in
with hypertriglyceridemia, rs7252453 in
with decreased risk to hypercholesterolemia and rs11076176 in
with increased risk to low high density lipoprotein cholesterol.
We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.
The total antioxidant capacity (TAC) has been related to the development of and complications associated with chronic diseases, but its importance during obesity is not entirely clear. We conducted a ...systematic review and meta-analysis to clarify whether there are differences or similarities in the TAC between subjects with obesity (SO) and subjects with normal weight (NW). Following the recommendations of PRISMA and Cochrane, we performed a systematic search in the PubMed, Scopus, Web of Science, Cochrane, and PROSPERO databases, identifying 1607 studies. Among these, 22 studies were included in the final analysis, comprising 3937 subjects (1665 SO and 2272 NW) in whom serum TAC was measured, and from these 19,201 subjects, the correlation of serum TAC with anthropo-metabolic parameters was also estimated. The Newcastle–Ottawa method was used for the evaluation of the risk of bias. Using a random-effect model (REM), TAC was reduced in SO independently of age (SMD, −0.86; 95% CI −1.38 to −0.34; p = 0.0012), whereas malondialdehyde (SMD, 1.50; 95% CI 0.60 to 2.41), oxidative stress index (SMD, 1.0; 95% CI 0.16 to 1.84), and total oxidant status (SMD, 0.80; 0.22 to 1.37) were increased. There were seven significant pooled correlations of TAC with anthropometric and metabolic parameters: weight (r = −0.17), hip circumference (r= −0.11), visceral adipose index (r = 0.29), triglycerides (r = 0.25), aspartate aminotransferase (r = 0.41), alanine aminotransferase (r = 0.38), and uric acid (r = 0.53). Our results confirm a decrease in TAC and an increase in markers of oxidative stress in SO and underpin the importance of these serum biomarkers in obesity.
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