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DNA methylation in aging and cancer. The different proteins playing a role in DNA methylation are shown with their reported molecular activity and cellular function. A summary of the changes observed in DNA methylation patterns during cancer and aging by different studies are also shown. Both changes at a global level and at specific gene promoters are indicated. ER, estrogen receptor; BRCA1, breast cancer 1; APC, adenomatosis polyposis coli.
Source publication
Aging is a multifaceted process characterized by genetic and epigenetic changes in the genome. The genetic component of aging received initially all of the attention. Telomere attrition and accumulation of mutations due to a progressive deficiency in the repair of DNA damage with age remain leading causes of genomic instability. However, epigenetic...
Contexts in source publication
Context 1
... methylation is one of the best understood modifica- tions of chromatin, with crucial roles in gene expression and imprinting, defense against viral sequences, inhibition of re- combination, as well as assembly of heterochromatin (11). Three active DNMT activities (DNMT1, DNMT3a, and DNMT3b) have been identified in humans and mice (93, 94) (Fig. 3). DNMT1 functions primarily as maintenance DNMT, responsible for copying the parental-strand DNA methylation pattern onto the daughter strand after each round of DNA replication. DNMT3a and DNMT3b function as de novo DNMTs, although they can also maintain methylation patterns. DNA methylation is associated with the induction of a ...
Context 2
... many of these promoters are also hypermethylated during tumorigenesis, suggesting a role in the increased cancer sus- ceptibility associated with aging. These different lines of evidence indicate that a global hypomethylation of the genome accompanies the aging pro- cess, concomitant with increased methylation of specific gene promoters (19,32) (Fig. 3). The molecular mechanisms behind these changes in DNA methylation patterns during aging re- main unknown. Transcriptional control of DNMTs was shown to be altered in aged and transformed human fibroblasts (21). In fact, it was proposed that the global decrease in DNA methylation could stem from a progressive decrease in the efficacy of ...
Context 3
... is characterized by global DNA hypomethylation and site-specific promoter hypermethylation (32, 60) (Fig. 3). DNA hypomethylation initiates chromosome instability and activates protooncogenes, increasing tumor frequency in mouse models (30,53). CpG islands located in gene promoters are unmethylated in normal tissues (12). De novo methylation of these islands occurs in a variety of tumors, leading to transcriptional repression of tumor ...
Citations
... These successes sparked the development of supervised ML methods for methylation calling on nanopore data [8][9][10][11]. The first methylation modification tackled by nanopore technology was 5-methylcytosine (5mC), a well-studied modification owing to its abundance in the human genome [12] and its links to a number of key biological processes such as ageing and cancer [13,14]. Indeed, nanopore-based methylation calling has been shown to be an effective tool in the classification of brain tumours [15]. ...
Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC) and N6-methyladenine (6mA). These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA k -mer backgrounds—a complete training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with hidden Markov models (HMMs) that cannot make successful calls for k -mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen k -mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM–DNN approach, amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. This type of approach is expected to be useful for calling other base modifications such as 5-hydroxymethylcytosine and for the simultaneous calling of different modifications, settings in which complete training data are not likely to be available.
... In response to this prevailing hypoxia, various oncogenic mechanisms come into play, with epigenetic mod-ifications taking a prominent role in promoting increased tumor growth and enhancing the survival of cancer cells [102]. These epigenetic changes encompass a wide spectrum of alterations, including hypomethylation, primarily activating oncogenes [103], gene-specific hypermethylation of CpG islands in the promoter regions of tumor suppressor genes, rendering them inactive, and contributing to aberrant cell proliferation [104]. Central to these processes are the ten-eleven translocation (TET) enzymes, a class of dioxygenases dependent on Fe 2+ and α-ketoglutarate. ...
Worldwide, hypoxia-related conditions, including cancer, COVID-19, and neuro-degenerative diseases, often lead to multi-organ failure and significant mortality. Oxygen, crucial for cellular function, becomes scarce as levels drop below 10 mmHg (<2% O2), triggering mitochondrial dysregulation and activating hypoxia-induced factors (HiFs). Herein, oxygen nanobubbles (OnB), an emerging versatile oxygen delivery platform, offer a novel approach to address hypoxia-related pathologies. This review explores OnB oxygen delivery strategies and systems, including diffusion, ultrasound, photodynamic, and pH-responsive nanobubbles. It delves into the nanoscale mechanisms of OnB, elucidating their role in mitochondrial metabolism (TFAM, PGC1alpha), hypoxic responses (HiF-1alpha), and their interplay in chronic pathologies including cancer and neurodegenerative disorders, amongst others. By understanding these dynamics and underlying mechanisms, this article aims to contribute to our accruing knowledge of OnB and the developing potential in ameliorating hypoxia- and metabolic stress-related conditions and fostering innovative therapies.
... Aging is a multifactorial biological process accompanied by alterations in molecular, cellular, and physiological functions in most living organisms, resulting in a progressive decline in overall fitness and, eventually, death. Accumulated evidence indicates that age-associated alterations in DNA methylation patterns, along with other epigenetic modifications such as histone modifications, chromatin remodeling, or non-coding RNAs, play a crucial role in aging and the development of age-related diseases [1]. To date, changes in DNA methylation levels of specific CpG sites are widely used as aging biomarkers to estimate an individual's age in prediction models, currently referred to as the epigenetic clock [2]. ...
Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert’s blood-based age prediction model to estimate the epigenetic age of 50 conditionally “healthy” and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20–60 years. The DNA methylation status of 4 CpG sites (ASPA CpG1, PDE4C CpG1, ELOVL2 CpG6, and EDARADD CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers. At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between “healthy” long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.
... DNAm is the process of covalent binding of the methyl group to C5 position of cytosine residues in cytosine-phosphate-guanine dinucleotide sequences (Handy et al. 2011). Animal model experiments have established the role of DNAm in aging and DNAm can be changed with geroprotective interventions, however, whether changes in DNAm affect all hallmarks of aging and how does that affect the aging trajectories remains unclear (Gonzalo 2010;Saul andKosinsky 2021, Yang et al. 2023). In humans, even though many intervention studies aim to assess biological age by DNAm in pos-hoc analysis, a few have incorporated it into the study design as responsive biomarker of ageing (Table 1) (Chen et al. 2019, Fahy et al. 2019, Fraszczyk et al. 2020, Gensous et al. 2020, Demidenko et al. 2021, Fiorito et al. 2021, Fitzgerald et al. 2021, Clement et al. 2022, Gensous et al. 2022, Waziry et al. 2023. ...
Chronological age is the most important risk factor for the incidence of age-related diseases. The pace of ageing determines the magnitude of that risk and can be expressed as biological age. Targeting fundamental pathways of human aging with geroprotectors has the potential to lower the biological age and therewith prolong the healthspan, the period of life one spends in good health. Target populations for geroprotective interventions should be chosen based on the ageing mechanisms being addressed and the expected effect of the geroprotector on the primary outcome. Biomarkers of ageing, such as DNA methylation age, can be used to select populations for geroprotective interventions and as a surrogate outcome. Here, the use of DNA methylation clocks for selecting target populations for geroprotective intervention is explored.
... Most somatic cells as well as primordial cells have global hypomethylation as they age [48,49]. Nevertheless, the overall methylation difference between elderly and young HSCs varies depending on the study. ...
One of the traits of cancer cells is abnormal DNA methylation patterns. The idea that age-related epigenetic changes may partially explain the increased risk of cancer in the elderly is based on the observation that aging is also accompanied by comparable changes in epigenetic patterns. Lineage bias and decreased stem cell function are signs of hematopoietic stem cell compartment aging. Additionally, aging in the hematopoietic system and the stem cell niche have a role in hematopoietic stem cell phenotypes linked with age, such as leukemia and lymphoma. Understanding these changes will open up promising pathways for therapies against age-related disorders because epigenetic mechanisms are reversible. Additionally, the development of high-throughput epigenome mapping technologies will make it possible to identify the “epigenomic identity card” of every hematological disease as well as every patient, opening up the possibility of finding novel molecular biomarkers that can be used for diagnosis, prediction, and prognosis.
... DNA methylation (DNAm), a chemical modification of DNA with a methyl group addition predominantly at a cytosine-phosphate-guanine (CpG) site [20], has been associated with poor health outcomes, such as cardiovascular diseases (CVDs), cancer, aging, oxidative stress, and inflammation [20][21][22][23][24]. Meanwhile, DNAm has been linked with PM 2.5 across different time windows [25][26][27][28]. ...
Background
Epigenome-wide association studies of ambient fine particulate matter (PM 2.5 ) have been reported. However, few have examined PM 2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources.
Methods
We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000–2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM 2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM 2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways.
Results
We included 669 men with 1,178 visits between 2000–2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic.
Conclusions
Our findings showed that the effects of PM 2.5 on DNAm varied by its PMCs and sources.
... On the other hand, alternative hypotheses suggest that hypomethylation is partially caused by random errors in the replication of methylation patterns from the template strand to the daughter strand or during the maintenance of methylation; however, these hypotheses fail to explain why such losses are site-specific [99,100]. Simultaneously, certain specific genomic areas are hypomethylated overtime to silence the expression of genes involved in transcription, tumor suppression, development, growth, and metabolism, suggesting that these changes could lead to enzymatic aberrations of DNMT and other related enzymes that, in turn, would generate anomalies in gene expression [101]. ...
Longevity has been a topic of interest since the beginnings of humanity, yet its aetiology and precise mechanisms remain to be elucidated. Aging is currently viewed as a physiological phenomenon characterized by the gradual degeneration of organic physiology and morphology due to the passage of time where both external and internal stimuli intervene. The influence of intrinsic factors, such as progressive telomere shortening, genome instability due to mutation buildup, the direct or indirect actions of age-related genes, and marked changes in epigenetic, metabolic, and mitochondrial patterns constitute a big part of its underlying endogenous mechanisms. On the other hand, several psychosocial and demographic factors, such as diet, physical activity, smoking, and drinking habits, may have an even more significant impact on shaping the aging process. Consequentially, implementing dietary and exercise patterns has been proposed as the most viable alternative strategy for attenuating the most typical degenerative aging changes, thus increasing the likelihood of prolonging lifespan and achieving successful aging.
... Age-related epigenetic changes contribute to the aging phenotype by promoting genomic instability, carcinogenesis, and cardiovascular pathologies (Pagiatakis et al., 2021). While human studies on this topic are limited to epigenome-wide association studies, experiments on model organisms find much more conclusive evidence for the driving role of DNAm in aging (Gonzalo, 2010;Saul and Kosinsky, 2021). Recent research has focused on identifying specific epigenetic changes associated with aging as well as the molecular mechanisms that drive these changes. ...
Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled geroscientists to study the underlying mechanisms of aging and assess the effectiveness of anti-aging therapies, including diet, exercise and environmental exposures. This review explores the effects of modifiable lifestyle factors' on the global DNA methylation landscape, as seen by aging clocks. We also discuss the underlying mechanisms through which these factors contribute to biological aging and provide comments on what these findings mean for people willing to build an evidence-based pro-longevity lifestyle.
... A hallmark change of aging is genome-wide DNA hypomethylation [126]. Accordingly, DNA methylation-based biomarkers have been evaluated for predicting age and are considered the most promising of six distinct age estimators [127]. ...
DNA methylation is the most stable epigenetic modification. In mammals, it usually occurs at the cytosine of CpG dinucleotides. DNA methylation is essential for many physiological and pathological processes. Aberrant DNA methylation has been observed in human diseases, particularly cancer. Notably, conventional DNA methylation profiling technologies require a large amount of DNA, often from a heterogeneous cell population, and provide an average methylation level of many cells. It is often not realistic to collect sufficient numbers of cells, such as rare cells and circulating tumor cells in peripheral blood, for bulk sequencing assays. It is therefore essential to develop sequencing technologies that can accurately profile DNA methylation using small numbers of cells or even single cells. Excitingly, many single-cell DNA methylation sequencing and single-cell omics sequencing technologies have been developed, and applications of these methods have greatly expanded our understanding of the molecular mechanism of DNA methylation. Here, we summaries single-cell DNA methylation and multi-omics sequencing methods, delineate their applications in biomedical sciences, discuss technical challenges, and present our perspective on future research directions.
... Hypomethylation of oncogenes and hypermethylation of tumor suppressors have been extensively regarded as important regulatory factors in the occurrence and progression of cancer [12]. DNA methylation means adding a methyl group to 5' cytosine of a CG dinucleotide, which is called CpG for short. ...
This work aimed to study the effect of NFE2 like bZIP transcription factor 3 (NFE2L3) on clear cell renal cell carcinoma (ccRCC) cells and whether NFE2L3 expression was mediated by DNA methylation. Twenty-one ccRCC patients were collected. The gene methylation and expression data of TCGA-KIRC were accessed from TCGA. Candidate methylation driver genes were identified by “MethylMix” package, and finally, NFE2L3 was selected as the target gene. The methylation of NFE2L3 was assayed by Ms PCR and QMSP. mRNA level of NFE2L3 was analyzed by qRT-PCR. Protein level of NFE2L3 was measured by Western blot. Demethylation was performed with methylation inhibitor 5-Aza-2’-deoxycytidine (5-Aza-CdR). Proliferative, migratory, and invasive abilities of ccRCC cells were assayed via cell colony formation assay, scratch healing assay, and transwell assay, respectively. Analysis of TCGA database presented that DNA hypomethylation occurred in the NFE2L3 promoter region in ccRCC tissues. NFE2L3 was significantly upregulated in ccRCC tissues and cells. Its expression in cells treated with 5-Aza-CdR was proportional to the concentration of methylation inhibitor. In cell function experiments, overexpressing NFE2L3 or demethylation could stimulate proliferation, migration, and invasion abilities of ccRCC and normal cells. 5-Aza-CdR treatment rescued repressive impact of knockdown NFE2L3 on malignant phenotypes of ccRCC and normal cells. DNA hypomethylation could induce high expression of NFE2L3 and facilitate malignant phenotypes of ccRCC cells. These results may generate insights into ccRCC therapy.
