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Aging Oct 2023The alcohol-associated biological aging remains to be studied across adulthood. We conducted linear regression analyses to investigate the associations between alcohol...
The alcohol-associated biological aging remains to be studied across adulthood. We conducted linear regression analyses to investigate the associations between alcohol consumption and two DNA methylation-based biological age acceleration metrics in 3823 Framingham Heart Study participants (24-92 years and 53.8% women) adjusting for covariates. We also investigated whether the two epigenetic aging metrics mediated the association of alcohol consumption with hypertension. We found that higher long-term average alcohol consumption was significantly associated with biological age acceleration assessed by GrimAge acceleration (GAA) and PhenoAge acceleration (PAA) in middle-aged (45-64 years, = 1866) and older (65-92 years, = 1267) participants while not in young participants (24-44 years, = 690). For example, one additional standard drink of alcohol (~14 grams of ethanol per day) was associated with a 0.71 ± 0.15-year ( = 2.1e-6) and 0.60 ± 0.18-year ( = 7.5e-4) increase in PAA in middle-aged and older participants, respectively, but the association was not significant in young participants ( = 0.23). One additional standard serving of liquor (~14 grams of ethanol) was associated with a greater increase in GAA (0.82-year, = 4.8e-4) and PAA (1.45-year, = 7.4e-5) than beer (GAA: 0.45-year, = 5.2e-4; PAA: 0.48-year, = 0.02) and wine (GAA: 0.51-year, = 0.02; PAA: 0.91-year, = 0.008) in middle-aged participant group. We observed that up to 28% of the association between alcohol consumption and hypertension was mediated by GAA or PAA in the pooled sample. Our findings suggest that alcohol consumption is associated with greater biological aging quantified by epigenetic aging metrics, which may mediate the association of alcohol consumption with quantitative traits, such as hypertension.
Topics: Humans; Female; Middle Aged; Aged; Adult; Aged, 80 and over; Male; Risk Factors; Alcohol Drinking; Aging; Hypertension; DNA Methylation; Ethanol; Epigenesis, Genetic
PubMed: 37889500
DOI: 10.18632/aging.205153 -
Epigenetics Dec 2024N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing...
N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.
Topics: Animals; RNA, Long Noncoding; RNA, Messenger; DNA Methylation; Colonic Neoplasms; Fluorouracil; Adenosine; Mammals
PubMed: 38145548
DOI: 10.1080/15592294.2023.2298058 -
Neurology Dec 2023There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau...
BACKGROUND AND OBJECTIVES
There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls.
METHODS
A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex.
RESULTS
The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at , , and genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, DNA methylation levels showed consistent association with AD.
DISCUSSION
These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD.
REGISTRATION INFORMATION
Research Ethics Committee of the University Hospital of Navarre (PI17/02218).
Topics: Humans; Female; Aged; Male; Alzheimer Disease; DNA Methylation; Case-Control Studies; Biomarkers; Genotype; tau Proteins; Amyloid beta-Peptides
PubMed: 37827850
DOI: 10.1212/WNL.0000000000207865 -
Nutrients Aug 2023Findings of epidemiologic studies focusing on the association between one-carbon metabolism-related micronutrients and breast cancer risk, along with the involvement of...
Findings of epidemiologic studies focusing on the association between one-carbon metabolism-related micronutrients and breast cancer risk, along with the involvement of DNA methylation, have been inconsistent and incomprehensive. We conducted a case-control study in China including 107 paired participants and comprehensively detected 12 plasma one-carbon metabolism-related micronutrients. Genomic DNA methylation was measured using an 850 K chip and differential methylation probes (DMPs) were identified. Multivariate logistic regression was performed to estimate the associations between plasma micronutrients and the odds of breast cancer. The mediation of selected DMPs in micronutrient breast cancer associations was examined using mediation analyses. An inverse association of plasma folate, methionine cycling-related micronutrients (methionine, S-adenosylmethionine, and S-adenosylhomocysteine), and all micronutrients in the choline metabolism and enzymatic factor groups, and a positive association of methionine cycling-related cysteine with breast cancer risk were observed. Nine micronutrients (methionine, cysteine, SAM, folate, choline, betaine, P5P, vitamins B, and B) were related to global or probe-specific methylation levels ( < 0.05). The selected DMPs mediated the micronutrient breast cancer associations with an average mediation proportion of 36.43%. This study depicted comprehensive associations between circulating one-carbon metabolism-related micronutrients and breast cancer risk mediated by DNA methylation.
Topics: Humans; Female; DNA Methylation; Breast Neoplasms; Micronutrients; Case-Control Studies; Cysteine; Trace Elements; Methionine; Racemethionine; S-Adenosylmethionine; Choline; Folic Acid; Carbon
PubMed: 37630812
DOI: 10.3390/nu15163621 -
International Journal of Cancer Oct 2023Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains...
Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains unclear. We conducted two-sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking-related DNA methylation to investigate their effect on 15 site-specific cancers, based on a genome-wide association study (GWAS) of 1.2 million European individuals and an epigenome-WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site-specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross-cancer effect were validated by overlapping with tissue-specific eQTLs. In the genomic MR, smoking measurements of smoking initiation, smoking cessation and LSI were suggested to be casually associated with risk of seven types of site-specific cancers, among which cancers at lung, cervix and colorectum were provided with strong evidence. In the epigenetic MR, methylation at 75 CpG sites were reported to be significantly associated with increased risks of multiple cancers. Eight out of 75 CpG sites were observed with cross-cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA-L) were validated by eQTLs at specific cancer sites, and cg07932199 (ATXN2) had strong evidence to be associated with cancers of lung (coefficient, 0.65, 95% confidence interval [CI], 0.31-1.00), colorectum (0.90 [0.61, 1.18]), breast (0.31 [0.20, 0.43]) and endometrium (0.98 [0.68, 1.27]). These findings highlight the potential practices targeting DNA methylation-involved cross-cancer pathways.
Topics: Female; Humans; DNA Methylation; Smoking; Genome-Wide Association Study; Mendelian Randomization Analysis; Neoplasms; CpG Islands
PubMed: 37449541
DOI: 10.1002/ijc.34656 -
Nature Communications Dec 2023Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome...
Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
Topics: Child; Humans; Wilms Tumor; Genotype; DNA Methylation; DNA; Kidney Neoplasms; Epigenesis, Genetic; Genomic Imprinting
PubMed: 38110397
DOI: 10.1038/s41467-023-43730-0 -
GeroScience Apr 2024Females live longer than males, and there are sex disparities in physical health and disease incidence. However, sex differences in biological aging have not been...
Females live longer than males, and there are sex disparities in physical health and disease incidence. However, sex differences in biological aging have not been consistently reported and may differ depending on the measure used. This study aimed to determine the correlations between epigenetic age acceleration (AA), and other markers of biological aging, separately in males and females. We additionally explored the extent to which these AA measures differed according to socioeconomic characteristics, clinical markers, and diseases. Epigenetic clocks (HorvathAge, HannumAge, PhenoAge, GrimAge, GrimAge2, and DunedinPACE) were estimated in blood from 560 relatively healthy Australians aged ≥ 70 years (females, 50.7%) enrolled in the ASPREE study. A system-wide deficit accumulation frailty index (FI) composed of 67 health-related measures was generated. Brain age and subsequently brain-predicted age difference (brain-PAD) were estimated from neuroimaging. Females had significantly reduced AA than males, but higher FI, and there was no difference in brain-PAD. FI had the strongest correlation with DunedinPACE (range r: 0.21 to 0.24 in both sexes). Brain-PAD was not correlated with any biological aging measures. Significant correlations between AA and sociodemographic characteristics and health markers were more commonly found in females (e.g., for DunedinPACE and systolic blood pressure r = 0.2, p < 0.001) than in males. GrimAA and Grim2AA were significantly associated with obesity and depression in females, while in males, hypertension, diabetes, and chronic kidney disease were associated with these clocks, as well as DunedinPACE. Our findings highlight the importance of considering sex differences when investigating the link between biological age and clinical measures.
Topics: Humans; Female; Male; Aged; Sex Characteristics; Australia; Brain; Aging; Australasian People
PubMed: 37747619
DOI: 10.1007/s11357-023-00941-z -
Frontiers in Endocrinology 2023Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine...
PURPOSE
Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients.
METHODS
OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis.
RESULTS
Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, =0.001) and P16 (OR=5.65, <0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, <0.001) and H4K16 (OR=6.03, <0.001) acetylation.
CONCLUSION
The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.
Topics: Humans; Thyroid Nodule; Lysine; DNA Methylation; Thyroid Neoplasms; Thyroid Cancer, Papillary; Epigenesis, Genetic; Pesticides
PubMed: 37560303
DOI: 10.3389/fendo.2023.1130794 -
PLoS Biology Oct 2023The N-terminal tails of eukaryotic histones are frequently posttranslationally modified. The role of these modifications in transcriptional regulation is...
The N-terminal tails of eukaryotic histones are frequently posttranslationally modified. The role of these modifications in transcriptional regulation is well-documented. However, the extent to which the enzymatic processes of histone posttranslational modification might affect metabolic regulation is less clear. Here, we investigated how histone methylation might affect metabolism using metabolomics, proteomics, and RNA-seq data from cancer cell lines, primary tumour samples and healthy tissue samples. In cancer, the expression of histone methyltransferases (HMTs) was inversely correlated to the activity of NNMT, an enzyme previously characterised as a methyl sink that disposes of excess methyl groups carried by the universal methyl donor S-adenosyl methionine (SAM or AdoMet). In healthy tissues, histone methylation was inversely correlated to the levels of an alternative methyl sink, PEMT. These associations affected the levels of multiple histone marks on chromatin genome-wide but had no detectable impact on transcriptional regulation. We show that HMTs with a variety of different associations to transcription are co-regulated by the Retinoblastoma (Rb) tumour suppressor in human cells. Rb-mutant cancers show increased total HMT activity and down-regulation of NNMT. Together, our results suggest that the total activity of HMTs affects SAM metabolism, independent of transcriptional regulation.
Topics: Humans; Methylation; Histones; Histone-Lysine N-Methyltransferase; Histone Methyltransferases; S-Adenosylmethionine; Protein Processing, Post-Translational; Neoplasms
PubMed: 37883365
DOI: 10.1371/journal.pbio.3002354 -
Nutrients Feb 2024Pregnancy is an extremely stressful period in a pregnant woman's life. Currently, women's awareness of the proper course of pregnancy and its possible complications is... (Review)
Review
Pregnancy is an extremely stressful period in a pregnant woman's life. Currently, women's awareness of the proper course of pregnancy and its possible complications is constantly growing. Therefore, a significant percentage of women increasingly reach for various dietary supplements during gestation. Some of the most popular substances included in multi-ingredient supplements are folic acid and choline. Those substances are associated with positive effects on fetal intrauterine development and fewer possible pregnancy-associated complications. Recently, more and more attention has been paid to the impacts of specific environmental factors, such as diet, stress, physical activity, etc., on epigenetic modifications, understood as changes occurring in gene expression without the direct alteration of DNA sequences. Substances such as folic acid and choline may participate in epigenetic modifications by acting via a one-carbon cycle, leading to the methyl-group donor formation. Those nutrients may indirectly impact genome phenotype by influencing the process of DNA methylation. This review article presents the current state of knowledge on the use of folic acid and choline supplementation during pregnancy, taking into account their impacts on the maternal-fetal unit and possible pregnancy outcomes, and determining possible mechanisms of action, with particular emphasis on their possible impacts on epigenetic modifications.
Topics: Pregnancy; Female; Humans; DNA Methylation; Dietary Supplements; Folic Acid; Epigenesis, Genetic; Choline
PubMed: 38474806
DOI: 10.3390/nu16050678