Hypomethylation Of Genes Research Articles

Differential methylation patterns in lean and obese non-alcoholic steatohepatitis-associated hepatocellular carcinoma

BackgroundNonalcoholic fatty liver disease affects about 24% of the world’s population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood.MethodsIn this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus obese mice. Differentially methylated regions were determined using reduced representation bisulfite sequencing.ResultsA larger number of differentially methylated regions (DMRs) were seen in NASH-HCC progression in the obese mice compared to the non-obese mice. No overlap existed in the DMRs with the largest methylation differences between the two models. In lean NASH-HCC, methylation differences were seen in genes involved with cancer progression and prognosis (including HCC), such as CHCHD2, FSCN1, and ZDHHC12, and lipid metabolism, including PNPLA6 and LDLRAP1. In obese NASH- HCC, methylation differences were seen in genes known to be associated with HCC, including RNF217, GJA8, PTPRE, PSAPL1, and LRRC8D. Genes involved in Wnt-signaling pathways were enriched in hypomethylated DMRs in the obese NASH-HCC.ConclusionsThese data suggest that differential methylation may play a role in hepatocarcinogenesis in lean versus obese NASH. Hypomethylation of Wnt signaling pathway-related genes in obese mice may drive progression of HCC, while progression of HCC in lean mice may be driven through other signaling pathways, including lipid metabolism.

Abstract 10922: Maternal Hypercholesterolemia Induces Changes in DNA Methylation Pattern of Lipid Metabolism Genes in the Human Placenta

Introduction: Maternal hypercholesterolemia (MHC) during gestation is reported to enhance formation of fatty streaks in human fetuses leading to atherosclerosis in their adulthood. As maternal lipid levels increase during gestation as a normal physiological response to growing fetus, cholesterol levels are not routinely monitored in the outpatient clinic. The mechanisms mediating the stimulus transferred from hypercholesterolemic mothers to the fetus resulting in atherogenesis remains to be delineated. Hypothesis: We hypothesize that high lipid levels of hypercholesterolemic mother program the fetus by causing changes in DNA methylation patterns of lipid transport and metabolism genes in the placenta. Methods: Pregnant females within 100 days of first pregnancy were recruited. Total cholesterol (TC) and Low Density Lipoprotein (LDL) levels above 200mg/dL and 130mg/dL respectively were considered as hypercholesterolemic (MHC; n=50). Pregnant mothers with normal cholesterol levels were also recruited (NC; n=50). Lipid profiling of maternal blood was performed in all trimesters. Cord blood at the time of birth and neonatal blood on the 2 nd day post birth were also profiled. DNA methylation array was performed in the placenta of MHC and NC mothers post delivery. Data were analyzed using RnBeads and Limma package. Data were validated by qRT PCR and immunohistochemistry of placental tissues. Results: Lipid profiling revealed high TC and LDL levels in MHC mothers and high triglycerides in their neonates on the 2 nd day post birth. There were 3789 differentially methylated gene sets reported in the placenta of hypercholesterolemic mothers of which, 167 genes were hypomethylated and 94 genes were hypermethylated in the CpG islands. The hypermethylation and downregulation of lysosomal lipase genes (LIPA) was observed in the placenta of MHC mothers. This was complemented by upregulated expression of PEX11A, a peroxisomal biogenesis factor and ABCD1 which is a fatty acid transporter. Conclusions: We report the hypermethylation of lysosomal lipid degradation genes and hypomethylation of peroxisomal genes in the placenta of MHC mothers. This results in high triglycerides in neonates with a risk for early atherogenesis in adulthood.

Insights Into the Role of DNA Methylation and Gene Expression in Graves Orbitopathy.

A role of DNA methylation in Graves orbitopathy (GO) has been proposed. This work aimed to investigate DNA methylation and gene expression in orbital fibroblasts from control and GO patients, under basal conditions or following challenge with an anti- thyrotropin (TSH) receptor antibody (M22) or cytokines involved in GO; to investigate the relationship between DNA methylation and cell function (proliferation); and to perform a methylome analysis. Orbital fibroblasts from 6 GO and 6 control patients from a referral center underwent methylome analysis of the whole genome. Global DNA methylation increased significantly both in control and GO fibroblasts on incubation with M22. Expression of 2 selected genes (CYP19A1 and AIFM2) was variably affected by M22 and interleukin-6. M22 increased cell proliferation in control and GO fibroblasts, which correlated with global DNA methylation. Methylome analysis revealed 19 869 DNA regions differently methylated in GO fibroblasts, encompassing 3957 genes and involving CpG islands, shores, and shelves. A total of 119 gene families and subfamilies, 89 protein groups, 402 biological processes, and 7 pathways were involved. Three genes found to be differentially expressed were concordantly hypermethylated or hypomethylated. Among the differently methylated genes, insulin-like growth factor-1 receptor and several fibroblast growth factors and receptors were included. We propose that, when exposed to an autoimmune environment, orbital fibroblasts undergo hypermethylation or hypomethylation of certain genes, involving CpG promoters, which results in differential gene expression, which may be responsible for functional alterations, in particular higher proliferation, and ultimately for the GO phenotype in vivo.

Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from invitro and invivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/β, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.

Emerging role of different DNA methyltransferases in the pathogenesis of cancer.

DNA methylation is one of the most essential epigenetic mechanisms to regulate gene expression. DNA methyltransferases (DNMTs) play a vital role in DNA methylation in the genome. In mammals, DNMTs act with some elements to regulate the dynamic DNA methylation patterns of embryonic and adult cells. Conversely, the aberrant function of DNMTs is frequently the hallmark in judging cancer, including total hypomethylation and partial hypermethylation of tumor suppressor genes (TSGs), which improve the malignancy of tumors, aggravate the ailment for patients, and significantly exacerbate the difficulty of cancer therapy. Since DNA methylation is reversible, currently, DNMTs are viewed as an important epigenetic target for drug development. However, the impression of DNMTs on cancers is still controversial, and therapeutic methods targeting DNMTs remain under exploration. This review mainly summarizes the relationship between the main DNMTs and cancers as well as regulatory mechanisms and clinical applications of DNMTs in cancer and highlights several forthcoming strategies for targeting DNMTs.

FCER1G Gene Hypomethylation in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that, when improperly treated, leads to disability in patients. Various factors that may cause the development and activity of RA are being considered. Epigenetic factors are also receiving increasing attention. In our study, we analyzed the association between FCER1G gene methylation and RA activity. We conducted our study in 50 RA patients and 24 controls. The patients were divided into two groups in terms of high disease activity and remission. Quantitative real-time methylation-specific PCR was used to analyze the methylation status of the investigated genes. We observed that RA patients have lower levels of methylation of the FCER1G gene compared to controls, but we did not find any difference in the methylation status of this gene between patients with high disease activity and remission. The results of this study suggest that FCER1G gene methylation may be a new potential epigenetic marker of RA that is independent of disease activity.

Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers.

Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via Tcell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-β, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.

Association of AGTR1 gene methylation and its genetic variant in Chinese farmer with hypertension: A case-control study.

The objective was to determine the potential associations of the angiotensin II receptor type 1 (AGTR1) gene polymorphism, methylation, and lipid metabolism in Chinese farmers with hypertension.A case-control study was conducted in Wuzhi county of Henan province in China in 2013 to 2014. A total of 1034 local residents (35–74 years, 386 hypertensive cases, and 648 normotensive subjects) were enrolled in this study. Triglyceride (TG), total cholesterol (TC), high-density lipoprotein, and low-density lipoprotein were measured using automatic chemistry analyzer. The AGTR1 gene promoter methylation level was measured using quantitative methylation-specific polymerase chain reaction method. The single nucleotide polymorphism rs275653 was genotyped with TaqMan probe assay at an applied biosystems platform.The gender, body mass index (BMI), TG, TC, and family history of hypertension in the hypertension group were significantly higher than those in control group (P < .05). No significant difference was observed in the distribution of AGTR1 rs275653 polymorphism in the hypertension and controls (P > .05). The AGTR1 gene methylation in subjects carrying different genotypes was not significantly observed (P > .05). The logistic regression analysis found the AGTR1 gene methylation level was negative correlation with hypertension in the present study (odds ratio, 0.946, 95% confidence interval, 0.896–0.999) through adjusting for age, gender, BMI, education, smoking, alcohol drinking, fruit and vegetable intake, pickles intake, and family history of hypertension.The association of AGTR1 gene hypomethylation and essential hypertension was observed in Chinese farmers; no significant difference was observed in the distribution of AGTR1 rs275653 polymorphism.

Multi-omic characterization of pediatric ARDS via nasal brushings

RationaleWhile nasal brushing transcriptomics can identify disease subtypes in chronic pulmonary diseases, it is unknown whether this is true in pediatric acute respiratory distress syndrome (PARDS).ObjectivesDetermine whether nasal transcriptomics and methylomics can identify clinically meaningful PARDS subgroups that reflect important pathobiological processes.MethodsNasal brushings and serum were collected on days 1, 3, 7, and 14 from control and PARDS subjects from two centers. PARDS duration was the primary endpoint.Measurements and main resultsTwenty-four control and 39 PARDS subjects were enrolled. Two nasal methylation patterns were identified. Compared to Methyl Subgroup 1, Subgroup 2 had hypomethylation of inflammatory genes and was enriched for immunocompromised subjects. Four transcriptomic patterns were identified with temporal patterns indicating injury, repair, and regeneration. Over time, both inflammatory (Subgroup B) and cell injury (Subgroup D) patterns transitioned to repair (Subgroup A) and eventually homeostasis (Subgroup C). When control specimens were included, they were largely Subgroup C. In comparison with 17 serum biomarkers, the nasal transcriptome was more predictive of prolonged PARDS. Subjects with initial Transcriptomic Subgroup B or D assignment had median PARDS duration of 8 days compared to 2 in A or C (p = 0.02). For predicting PARDS duration ≥ 3 days, nasal transcriptomics was more sensitive and serum biomarkers more specific.ConclusionsPARDS nasal transcriptome may reflect distal lung injury, repair, and regeneration. A combined nasal PCR and serum biomarker assay could be useful for predictive and diagnostic enrichment.Trial registration Clinicaltrials.gov NCT03539783 May 29, 2018.

Heparanase Gene Hypomethylation as a Potential Biomarker for Precision Screening of Bladder Cancer

Background: Epigenetics has been playing an increasingly important role in the study of the origin and development of bladder cancer (BC). This study aimed to investigate the correlation between promoter hypomethylation of the heparanase (HPSE) gene and clinicopathologic characteristics of bladder cancer (BC). Materials and Methods: The promoter hypomethylation profile was evaluated by methylation-specific polymerase chain reaction (PCR) using 27 BC tissue specimens and 15 normal control specimens. The aim was to help decipher the underlying relationship between the clinicopathologic characteristics and the hypomethylation status. Results: Experimental results showed that 16 (59.26%) BC specimens demonstrated the promoter hypomethylation of HPSE, including 2 cases with complete demethylation. For normal control groups, only 3 specimens (20%) indicated hypomethylation (P&lt;0.05). In addition, the occurrence of hypomethylation increased with the metastasis of positive lymph nodes (P&lt;0.05). Importantly, no significant correlation was found between the hypomethylation of HPSE and the profile of patients including gender, age, tumor size, cancer stage, or histologic grade (P&gt;0.05). Conclusion: The promoter hypomethylation of HPSE gene is a common epigenetic event occurring in BC and is positively correlated with a poor prognosis. This study suggested that the promoter hypomethylation could be used as a potential biological marker for the early screening of BC.

Epigenetic Aspects and Prospects in Autoimmune Hepatitis.

The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.

Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature

ObjectivesLupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional lupus-associated DNA methylation changes and determine the...

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS

AbstractPeripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL–not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Transcriptome-Wide N6-Methyladenosine Methylome Alteration in the Rat Spinal Cord After Acute Traumatic Spinal Cord Injury.

Recent studies showed that RNA N6-methyladenosine (m6A) plays an important role in neurological diseases. We used methylated RNA immunoprecipitation sequencing (MeRIP-Seq) technology to generate the m6A modification map after traumatic spinal cord injury (TSCI). A total of 2,609 differential m6A peaks were identified after TSCI. Our RNA sequencing results after TSCI showed 4,206 genes with significantly altered expression. Cross-link analysis of m6A sequencing results and RNA sequencing results showed that 141 hyper-methylated genes were upregulated, 53 hyper-methylated genes were downregulated, 57 hypo-methylated genes were upregulated, and 197 hypo-methylated genes were downregulated. Among these, the important inflammatory response factor Tlr4 and the important member of the neurotrophin family Ngf were both upregulated and hyper-methylated after TSCI. This study provides that in the future, the epigenetic modifications of the genes could be used as an indicator of TSCI.

The impact of different feeds on DNA methylation, glycolysis/gluconeogenesis signaling pathway, and gene expression of sheep muscle.

DNA methylation is an important epigenetic regulatory form that regulates gene expression and tissue development. This study compared the effects of high fiber, low protein (HFLP) and low fiber, high protein (LFHP) diets on the DNA methylation profile of twin lambs’ muscles, their effect on glycolysis/gluconeogenesis and related pathways by transcriptome and deep whole-genome bisulfite sequencing (WGBS). Results identified 1,945 differentially methylated regions (DMRs) and 1,471 differentially methylated genes (DMGs). Also, 487 differentially expressed transcripts belonging to 368 differentially expressed genes (DEGs) were discovered between the twin lambs under different diets. Eleven overlapped genes were detected between the DEGs and the DMGs. FKBP5 and FOXO1 were detected to be significantly different. The FOXO1 regulated cAMP and the glycolysis/gluconeogenesis pathways. The glycolysis/gluconeogenesis, and the FOXO pathways were significantly enriched. The expressions of HOMER1 and FOXO1 in the HFLP group were significantly higher than those in the LFHP group. There is a significant correlation between the upregulated gene expression and hypomethylation of HOMER1 and FOXO1 gene in HFLP group. The results showed that FOXO1 induces PDK4 expression in muscle while regulating FKBP5 activity, which stimulates glucose production by activating specific gluconeogenesis target genes. The FOXO1 was able to regulate the glucose metabolism, the cAMP and the occurrence of glycolysis/gluconeogenesis pathways. This study showed that feed type can affect the methylation levels of the glycolysis related gluconeogenesis genes and interaction pathways, providing new ideas for a better understanding of the regulation of muscle energy metabolism and feed development.

Clozapine Long-Term Treatment Might Reduce Epigenetic Age Through Hypomethylation of Longevity Regulatory Pathways Genes.

Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed using the Infinium MethylationEPIC BeadChip in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models. The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein–protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes.

DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling

ABSTRACTThe earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition during vertebrate embryogenesis. Notch signaling is crucial for HSPC generation across vertebrates; however, the precise control of Notch during this process remains unclear. In the present study, we used multi-omics approaches together with functional assays to assess global DNA methylome dynamics during the endothelial cells to HSPCs transition in zebrafish, and determined that DNA methyltransferase 1 (Dnmt1) is essential for HSPC generation via repression of Notch signaling. Depletion of dnmt1 resulted in decreased DNA methylation levels and impaired HSPC production. Mechanistically, we found that loss of dnmt1 induced hypomethylation of Notch genes and consequently elevated Notch activity in hemogenic endothelial cells, thereby repressing the generation of HSPCs. This finding deepens our understanding of HSPC specification in vivo, which will provide helpful insights for designing new strategies for HSPC generation in vitro.

Comprehensive analysis of DNA methylation for periodontitis

BackgroundPeriodontitis is an infectious disease, and a risk factor for peri-implantitis that could result in the implant loss. DNA methylation has an essential role in the etiology and pathogenesis of inflammatory disease. However, there is lack of study on methylation status of genes in periodontitis. This study sought to explore the gene methylation profiling microarray in periodontitis.MethodsThrough searching in the Gene Expression Omnibus database, a gene methylation profiling data set GSE173081 was identified, which included 12 periodontitis samples and 12 normal samples, respectively. Thereafter, the data of GSE173081 was downloaded and analyzed to determined differentially methylated genes (DMGs), which then were used to perform Gene Ontology analysis and pathway enrichment analyses through online database. In addition, the DMGs were applied to construct the protein–protein interaction (PPI) network information, predict the hub genes in pathology of periodontitis.ResultsIn total 668 DMGs were sorted and identified from the data set, which included 621 hypo-methylated genes and 47 hyper-methylated genes. Through the function and ontology analysis, these 668 genes are mainly classified into intracellular signaling pathway, cell components, cell–cell interaction, and cellular behaviors. The pathway analysis showed that the hypo-methylated genes were mostly enriched in the pathway of cGMP–PKG signaling pathway; RAF/MAP kinase; PI3K–Akt signaling pathway, while hyper-methylated genes were mostly enriched in the pathway of bacterial invasion of epithelial cells; sphingolipid signaling pathway and DCC mediated attractive signaling. The PPI network contained 630 nodes and 1790 interactions. Moreover, further analysis identified top 10 hub genes (APP; PAX6; LPAR1; WNT3A; BMP2; PI3KR2; GATA4; PLCB1; GATA6; CXCL12) as central nodes that are involved in the immune system and the inflammatory response.ConclusionsThis study provides comprehensive information of methylation status of genes to the revelation of periodontitis pathogenesis that may contribute to future research on periodontitis.

Effects of different types of resistance exercise failure training on the methylation status of genes that drive skeletal muscle hypertrophy

ObjectiveWe sought to determine how one bout of resistance training to failure with either higher repetitions (30FAIL) or lower repetitions (80FAIL) affected the promoter methylation statuses of genes that drive skeletal muscle hypertrophy.HypothesesWe hypothesized that a bout of 80FAIL training would lead to a more robust hypomethylation of genes that regulate skeletal muscle hypertrophy compared to 30FAIL training.MethodsEleven previously‐trained college‐aged men (age: 23 ± 4 years, 11.42 ± 6.38 percent fat, 4 ± 3 years training experience) volunteered for this study. Each participant underwent two training bouts (spaced one week apart) involving either: i) 30FAIL training; 4 sets of back squats and 4 sets of leg extensors to failure at 30% of one‐repetition maximum (1RM), or: ii) 80FAIL training; 4 sets of both exercises at 80% of 1RM. Muscle biopsies from the vastus lateralis were collected prior to each bout (PRE), 3 hours following each bout (3hPOST), and 6 hours following each bout (6hPOST). Following the conclusion of the study, tissue was batch‐processed for DNA isolation, and DNA was subjected to the Illumina MethylationEPIC array. In an a priori fashion, genes that have been shown to induce skeletal muscle hypertrophy in genetic mouse models were the target of this investigation (Verbrugge et al. Frontiers Physiol, 2019).ResultsTotal training volume (sets x reps x load) between the 30FAIL and 80FAIL bouts were not significantly different (p= 0.571). Differentially methylated region changes for the following genes from PRE to 3hPOST and PRE to 6hPOST are presented herein: SKI, FST, AKT1, ACVR2B, MSTN, KLF10, RHEB, IGF1, PAPPA, PPARD, IKBKB, FSTL3, ATGR1, UCN3, MCU, JUNB, NCOR1, GPRASP1, GRB10, MMP9, DGKZ, PPARGC1A, SMAD4, LTBP4, BMPR1A, CRTC2, XIAP, DGAT1, THRA, ADRB2, ASB15, CAST, EIF2B5, BDKRB2, TPT1, NR3C1, NR4A1, GNAS, PLD1, CRYM, CAMKK1, YAP1, INHBA, TP53INP2, INHBB, NOL3, and ESR1. Additionally, significant differences between conditions at each time point are highlighted.ConclusionsThis study continues to display how different modalities of resistance training affect the skeletal muscle molecular milieu and furthers our scientific understanding of factors that contribute to training adaptations.

Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.