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BMC Genomic Data Aug 2023Sarcopenia is a disease diagnosed in the elderly. In patients with sarcopenia, the muscle mass decreases every year. The occurrence of sarcopenia is greatly affected by...
BACKGROUND
Sarcopenia is a disease diagnosed in the elderly. In patients with sarcopenia, the muscle mass decreases every year. The occurrence of sarcopenia is greatly affected by extrinsic factors such as eating habits, exercise, and lifestyle. The present study aimed to determine the relationship between muscle mass traits and genes affected by epigenetic factors with three different adjustment methods using Korean Genome and Epidemiology Study (KOGES) data.
RESULTS
We conducted a demographic study and DNA methylation profiling by three studies according to the muscle mass index (MMI) adjustment methods: appendicular skeletal muscle mass divided by body weight (MMI1); appendicular skeletal muscle mass divided by square of height (MMI2); appendicular skeletal muscle mass divided by BMI (MMI3). We analyzed differentially methylated regions (DMRs) for each group. We then restricted our subjects to be top 30% (T30) and bottom 30% (B30) based on each MMI adjustment method. Additionally, we performed enrichment analysis using PathfindR to evaluate the relationship between identified DMRs and sarcopenia. A total of 895 subjects were included in the demographic study. The values of BMI, waist, and hip showed a significant difference in all three groups. Among 446 participants, 44 subjects whose DNA methylation profiles were investigated were included for DNA methylation analysis. The results of enrichment analysis showed differences between groups. In the women group through MMI1 method, only the glutamatergic synapse pathway showed a significant result. In the men group through MMI2 method, the adherens junction pathway was the most significant. Women group through MMI2 method showed similar results, having an enriched Rap1 signaling pathway. In men group through MMI3 method, the Fc epsilon RI signaling pathway was the most enriched. Particularly, the notch signaling pathway was significantly enriched in women group through MMI3 method.
CONCLUSION
This study presents results about which factor should be concerned first in muscle mass index (MMI) adjustment. The present study suggested that GAB2 and JPH3 in MMI1 method, HLA-DQB1 and TBCD in MMI2 method, GAB2, NDUFB4 and ISPD in MMI3 method are potential genes that can have an impact on muscle mass. It could enable future epigenetic studies of genes based on annotation results. The present study is a nationwide study in Korea with the largest size up to date that compares adjustment indices for MMI in epigenetic research.
Topics: Aged; Female; Humans; Male; Adherens Junctions; DNA Methylation; Microtubule-Associated Proteins; Muscle, Skeletal; Sarcopenia
PubMed: 37653517
DOI: 10.1186/s12863-023-01152-3 -
Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.Epigenetics Dec 2023Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its...
Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 μg/dL] and High DHEAS (HD) [≥42 μg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.
Topics: Female; Humans; Child; Adrenarche; Androgens; Pilot Projects; DNA Methylation; Dehydroepiandrosterone Sulfate; Obesity
PubMed: 37053179
DOI: 10.1080/15592294.2023.2200366 -
Orphanet Journal of Rare Diseases Aug 2023One of the most prevalent cancers in the world is lung cancer, with adenocarcinoma (LUAD) making up a significant portion of cases. According to the National Cancer...
BACKGROUND
One of the most prevalent cancers in the world is lung cancer, with adenocarcinoma (LUAD) making up a significant portion of cases. According to the National Cancer Institute (NCI), there are new cases and fatality rates per 100,000 individuals as follows: New instances of lung and bronchial cancer occur annually at a rate of 50.0 per 100,000 persons. The yearly death rate for men and women is 35.0 per 100,000. DNA methylation is one of the earliest discovered and widely studied epigenetic regulatory mechanisms, and its abnormality is closely related to the occurrence and development of cancer. However, the prognostic value of DNA methylation and LUAD needs to be further explored to improve the survival prediction of LUAD patients.
METHODS
The transcriptome data and clinical data of LUAD were downloaded from TCGA and GEO databases, and the Illumina Human Methylation450 array (450k array) data were downloaded from the TCGA database. Firstly, the intersection of the expressed genes of the two databases is corrected, the differential analysis is performed, and the methylation data is evaluated by the MethylMix package to obtain differentially methylated genes. Independent prognostic genes were screened out using univariate and multivariate Cox regression analysis, and a methylation prognostic model was developed using univariate Cox analysis and validated with the GSE30219 dataset in the GEO database. Survival analysis between methylation high-risk and low-risk groups was performed and a methylation-based gene prognostic model was constructed. Finally, the prediction of potential drugs associated with the LUAD gene signature using Drug Sensitivity Genomics in Cancer (GDSC).
RESULTS
In this study, a total of 555 samples from the TCGA database and 307 samples from GSE30219 were included, and a total of 24 differential methylation driver genes were identified. Univariate and multivariate Cox regression analyzes were used to screen out independent prognostic genes, involving 2 genes: CFTR, PKIA. Survival analysis was different between the methylation high-risk group and the low-risk group, the CFTR high methylation group and the low methylation group were poor, and the opposite was true for PKIA.
CONCLUSIONS
Our study revealed that the methylation status of CFTR and PKIA can serve as potential prognostic biomarkers and therapeutic targets in lung cancer.
Topics: Male; Humans; Female; Methylation; Cystic Fibrosis Transmembrane Conductance Regulator; Adenocarcinoma of Lung; Lung Neoplasms; Biomarkers
PubMed: 37644544
DOI: 10.1186/s13023-023-02807-1 -
METTL3 from Target Validation to the First Small-Molecule Inhibitors: A Medicinal Chemistry Journey.Journal of Medicinal Chemistry Feb 2023RNA methylation is a critical mechanism for regulating the transcription and translation of specific sequences or for eliminating unnecessary sequences during RNA... (Review)
Review
RNA methylation is a critical mechanism for regulating the transcription and translation of specific sequences or for eliminating unnecessary sequences during RNA maturation. METTL3, an RNA methyltransferase that catalyzes the transfer of a methyl group to the -adenosine of RNA, is one of the key mediators of this process. METTL3 dysregulation may result in the emergence of a variety of diseases ranging from cancer to cardiovascular and neurological disorders beyond contributing to viral infections. Hence, the discovery of METTL3 inhibitors may assist in furthering the understanding of the biological roles of this enzyme, in addition to contributing to the development of novel therapeutics. Through this work, we will examine the existing correlations between METTL3 and diseases. We will also analyze the development, mode of action, pharmacology, and structure-activity relationships of the currently known METTL3 inhibitors. They include both nucleoside and non-nucleoside compounds, with the latter comprising both competitive and allosteric inhibitors.
Topics: Chemistry, Pharmaceutical; RNA, Messenger; Methyltransferases; Methylation; RNA
PubMed: 36692498
DOI: 10.1021/acs.jmedchem.2c01601 -
Ecotoxicology and Environmental Safety May 2023Accumulating evidence has demonstrated that N6-methyladenosine (mA) plays important roles in a variety of diseases. However, the specific functions of mA in CdCl-induced...
BACKGROUND
Accumulating evidence has demonstrated that N6-methyladenosine (mA) plays important roles in a variety of diseases. However, the specific functions of mA in CdCl-induced kidney injury remain unclear.
OBJECTIVE
Here, we investigate a transcriptome-wide map of mA modifications and explore the effects of mA on Cd-induced kidney injury.
MATERIALS AND METHODS
The rat kidney injury model was constructed by subcutaneous injection of CdCl (0.5, 1.0, and 2.0 mg/kg). The mA levels were measured by colorimetry. The level of expression of mA-related enzymes were detected by reverse transcription quantitative real-time PCR analysis. Transcriptome-wide mA methylome in CdCl (2.0 mg/kg) and the control group were profiled by methylated RNA immunoprecipitation sequencing (MeRIP-seq). Subsequently, the sequencing data were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) confirmed the functional enrichment pathways of sequencing genes. In addition, a protein-protein interaction (PPI) network was applied to select hub genes.
RESULTS
The levels of mA and mA regulators (METTL3, METTL14, WTAP, YTHDF2) were significantly increased in CdCl groups. We identified a total of 2615 differentially expressed mA peaks, 868 differentially expressed genes and 200 genes with significant changes in both mA modification and gene expression levels. GO, KEGG, and GSEA analyses indicated that these genes were mainly enriched in inflammation and metabolism-related pathways such as in IL-17 signaling and fatty acid metabolism. According the result of the conjoint analysis, we identified the top ten hub genes (Fos, Hsp90aa1, Gata3, Fcer1g, Cftr, Cspg4, Atf3, Cdkn1a, Ptgs2, and Npy) which may be regulated by mA and involve in CdCl-induced kidney damage.
CONCLUSION
This study established a mA transcriptional map in a CdCl-induced kidney injury model and suggested that mA may affect CdCl induced kidney injury via regulated the inflammation and metabolism related gene.
Topics: Animals; Rats; Methylation; Cadmium; Transcriptome; Cyclic AMP Response Element-Binding Protein; Kidney
PubMed: 37054473
DOI: 10.1016/j.ecoenv.2023.114903 -
Brazilian Journal of Cardiovascular... Feb 2023Knockdown of fat mass and obesity-associated gene (FTO) can induce N6-methyladenosine (mA) ribonucleic acid (RNA) methylation. The objective of this study was to explore...
INTRODUCTION
Knockdown of fat mass and obesity-associated gene (FTO) can induce N6-methyladenosine (mA) ribonucleic acid (RNA) methylation. The objective of this study was to explore the effect of m 6A RNA methylation on atherosclerotic vulnerable plaque by FTO knockdown.
METHODS
A total of 50 New Zealand white rabbits were randomly divided into pure high-fat group, sham operation group, vulnerable plaque group, empty load group, and FTO knockdown group (10 rabbits/group).
RESULTS
Flow cytometry showed that helper T (Th) cells in the FTO knockdown group accounted for a significantly higher proportion of lymphocytes than in the vulnerable plaque group and empty load group (P<0.05). Th cells were screened by cell flow. The level of mA RNA methylation in the FTO knockdown group was significantly higher than in the vulnerable plaque group and empty load group (P<0.05). The levels of total cholesterol, triglyceride, and low-density lipoprotein C were higher at the 12 week than at the 1 week, but the high-density lipoprotein C level was lower at the 12 week than at the 1 week. At the 12th week, the interleukin-7 level was significantly lower in the adeno-associated virus-9 (AVV9)-FTO short hairpin RNA group than in the control and AVV9-green fluorescent protein groups (P<0.001).
CONCLUSION
After successfully establishing a vascular parkinsonism rabbit model, mA RNA methylation can decrease Th cells and vulnerable atherosclerotic plaques.
Topics: Rabbits; Animals; RNA; Plaque, Atherosclerotic; Methylation; T-Lymphocytes
PubMed: 35675496
DOI: 10.21470/1678-9741-2021-0039 -
Annual Review of Public Health Apr 2022Longstanding racial/ethnic inequalities in morbidity and mortality persist in the United States. Although the determinants of health inequalities are complex, social and... (Review)
Review
Longstanding racial/ethnic inequalities in morbidity and mortality persist in the United States. Although the determinants of health inequalities are complex, social and structural factors produced by inequitable and racialized systems are recognized as contributing sources. Social epigenetics is an emerging area of research that aims to uncover biological pathways through which social experiences affect health outcomes. A growing body of literature links adverse social exposures to epigenetic mechanisms, namely DNA methylation, offering a plausible pathway through which health inequalities may arise. This review provides an overview of social epigenetics and highlights existing literature linking social exposures-i.e., psychosocial stressors, racism, discrimination, socioeconomic position, and neighborhood social environment-to DNA methylation in humans. We conclude with a discussion of social epigenetics as a mechanistic link to health inequalities and provide suggestions for future social epigenetics research on health inequalities.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenomics; Health Status Disparities; Humans; Racial Groups; United States
PubMed: 35380065
DOI: 10.1146/annurev-publhealth-052020-105613 -
Epigenetics Dec 2023N6-Methyladenosine (mA) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs....
N6-Methyladenosine (mA) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs. However, little is known about the underlying mechanisms of mA-modified mRNAs in hepatic IR injury. In mouse models, liver samples were subjected to methylated RNA immunoprecipitation with high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). In total, 16917 mA peaks associated with 4098 genes were detected in the sham group, whereas 21,557 mA peaks associated with 5322 genes were detected in the IR group. There were 909 differentially expressed mA peaks, 863 differentially methylated transcripts and 516 differentially mA modification genes determined in both groups. The distribution of mA peaks was especially enriched in the coding sequence and 3'UTR. Furthermore, we identified a relationship between differentially mA methylated genes (fold change≥1.5/≤ 0.667, value≤0.05) and differentially expressed genes (fold change≥1.5 and value≤0.05) to obtain three overlapping predicted target genes (Fnip2, Phldb2, and Pcf11). Our study revealed a transcriptome-wide map of mA mRNAs in hepatic IR injury and might provide a theoretical basis for future research in terms of molecular mechanisms.
Topics: Animals; Mice; Transcriptome; DNA Methylation; Protein Processing, Post-Translational; 3' Untranslated Regions; RNA, Messenger; Reperfusion Injury
PubMed: 37066716
DOI: 10.1080/15592294.2023.2201716 -
Nature Communications May 2022Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA...
Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. Similar processes in mammals can also affect phenotype through intergenerational or trans-generational mechanisms. Here we generate a luciferase knock-in reporter mouse for the imprinted Dlk1 locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternal Dlk1 in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneous Dlk1 mis-expression is seen exclusively among animals born to F1-exposed females. Oocytes from these females show altered gene and microRNA expression without changes in DNA methylation, and correct imprinting is restored in subsequent generations. Our results illustrate how diet impacts the foetal epigenome, disturbing canonical and non-canonical imprinting mechanisms to modulate the properties of successive generations of offspring.
Topics: Animals; Biological Variation, Population; DNA Methylation; Diet, High-Fat; Epigenesis, Genetic; Female; Genomic Imprinting; Mammals; Mice; Pregnancy
PubMed: 35513363
DOI: 10.1038/s41467-022-30022-2 -
Dental Materials : Official Publication... May 2021The stability of the bond between polymeric adhesives to mineralized substrates is crucial in many biomedical applications. The objective of this study was to determine...
UNLABELLED
The stability of the bond between polymeric adhesives to mineralized substrates is crucial in many biomedical applications. The objective of this study was to determine the effect of methyl substitution at the α- and β-carbons on the kinetics of polymerization, monomer hydrolytic stability, and long-term bond strength to dentin for methacrylamide- and methacrylate-based crosslinked networks for dental adhesive applications.
METHODS
Secondary methacrylamides (α-CH substituted=1-methyl HEMAM, β-CH substituted=2-methyl HEMAM, and unsubstituted=HEMAM) and OH-terminated methacrylates (α- and β-CH mixture=1-methyl HEMA and 2-methyl HEMA, and unsubstituted=HEMA) were copolymerized with urethane dimethacrylate. The kinetics of photopolymerization were followed in real-time using near-IR spectroscopy. Monomer hydrolysis kinetics were followed by NMR spectroscopy in water at pH 1 over 30 days. Solvated adhesives (40 vol% ethanol) were used to bond composite to dentin and microtensile bond strength (μTBS) measured after 24h and 6 months storage in water at 37°C.
RESULTS
The rate of polymerization increased in the following order: OH-terminated methacrylates≥methacrylamides>NH-terminated methacrylates, with minimal effect of the substitution. Final conversion ranged between 79% for 1-methyl AEMA and 94% for HEMA. 1-methyl-HEMAM showed the highest and most stable μTBS, while HEMA showed a 37% reduction after six months All groups showed measurable degradation after up to 4 days in pH 1, with the methacrylamides showing less degradation than the methacrylates. Additionally, transesterification products were observed in the methacrylamide groups.
SIGNIFICANCE
Amide monomers were significantly more stable to hydrolysis than the analogous methacrylates. The addition of a α- or β-CH groups increased the rate of hydrolysis, with the magnitude of the effect tracking with the expected base-catalyzed hydrolysis of esters or amides, but opposite in influence. The α-CH substituted secondary methacrylamide, 1-methyl HEMAM, showed the most stable adhesive interface. A side reaction was observed with transesterification of the monomers studied under ambient conditions, which was not expected under the relatively mild conditions used here, which warrants further investigation.
Topics: Acrylamides; Composite Resins; Dental Bonding; Dental Cements; Dentin; Dentin-Bonding Agents; Materials Testing; Methacrylates; Methylation; Resin Cements; Tensile Strength
PubMed: 33663882
DOI: 10.1016/j.dental.2021.02.004