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Aging Cell Oct 2022Aging and cancer are clearly associated processes, at both the epidemiological and molecular level. Epigenetic mechanisms are good candidates to explain the molecular... (Review)
Review
Aging and cancer are clearly associated processes, at both the epidemiological and molecular level. Epigenetic mechanisms are good candidates to explain the molecular links between the two phenomena, but recent reports have also revealed considerable differences, particularly regarding the loss of DNA methylation in the two processes. The large-scale generation and availability of genome-wide epigenetic data now permits systematic studies to be undertaken which may help clarify the similarities and differences between aging and cancer epigenetic alterations. In addition, the development of epigenetic clocks provides a new dimension in which to investigate diseases at the molecular level. Here, we examine current and future questions about the roles of DNA methylation mechanisms as causal factors in the processes of aging and cancer so that we may better understand if and how aging-associated epigenetic alterations lead to tumorigenesis. It seems certain that comprehending the molecular mechanisms underlying epigenetic clocks, especially with regard to somatic stem cell aging, combined with applying single-cell epigenetic-age profiling technologies to aging and cancer cohorts, and the integration of existing and upcoming epigenetic evidence within the genetic damage models of aging will prove to be crucial to improving understanding of these two interrelated phenomena.
Topics: Aging; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Neoplasms
PubMed: 36103298
DOI: 10.1111/acel.13709 -
The Journal of Biological Chemistry Dec 2019DNA methylation and histone modifications critically regulate the expression of many genes and repeat regions during spermatogenesis. However, the molecular details of...
DNA methylation and histone modifications critically regulate the expression of many genes and repeat regions during spermatogenesis. However, the molecular details of these processes in male germ cells remain to be addressed. Here, using isolated murine sperm cells, ultra-low-input native ChIP-Seq (ULI-NChIP-Seq), and whole genome bisulfite sequencing (WGBS), we investigated genome-wide DNA methylation patterns and histone 3 Lys-9 trimethylation (H3K9me3) modifications during mouse spermatogenesis. We found that DNA methylation and H3K9me3 have distinct sequence preferences and dynamics in promoters and repeat elements during spermatogenesis. H3K9me3 modifications in histones at gene promoters were highly enriched in round spermatids. H3K9me3 modification on long terminal repeats (LTRs) and long interspersed nuclear elements (LINEs) was involved in silencing active transcription from these regions in conjunction with reestablishment of DNA methylation. Furthermore, H3K9me3 remodeling on the X chromosome was involved in meiotic sex chromosome inactivation and in partial transcriptional reactivation of sex chromosomes in spermatids. Our findings also revealed the DNA methylation patterns and H3K9me3 modification profiles of paternal and maternal germline imprinting control regions (gICRs) during spermatogenesis. Taken together, our results provide a genome-wide map of H3K9me3 modifications during mouse spermatogenesis that may be helpful for understanding male reproductive disorders.
Topics: Animals; DNA Methylation; Epigenomics; Histones; Male; Mice; Protein Processing, Post-Translational; Spermatogenesis; Terminal Repeat Sequences
PubMed: 31662436
DOI: 10.1074/jbc.RA119.010496 -
Aging Cell Oct 2021Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting... (Randomized Controlled Trial)
Randomized Controlled Trial
Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.
Topics: Aging; DNA Methylation; Diet Therapy; Exercise; Female; Humans; Male; Time Factors
PubMed: 34535961
DOI: 10.1111/acel.13439 -
Nature Methods May 2021Bacterial DNA methylation occurs at diverse sequence contexts and plays important functional roles in cellular defense and gene regulation. Existing methods for...
Bacterial DNA methylation occurs at diverse sequence contexts and plays important functional roles in cellular defense and gene regulation. Existing methods for detecting DNA modification from nanopore sequencing data do not effectively support de novo study of unknown bacterial methylomes. In this work, we observed that a nanopore sequencing signal displays complex heterogeneity across methylation events of the same type. To enable nanopore sequencing for broadly applicable methylation discovery, we generated a training dataset from an assortment of bacterial species and developed a method, named nanodisco ( https://github.com/fanglab/nanodisco ), that couples the identification and fine mapping of the three forms of methylation into a multi-label classification framework. We applied it to individual bacteria and the mouse gut microbiome for reliable methylation discovery. In addition, we demonstrated the use of DNA methylation for binning metagenomic contigs, associating mobile genetic elements with their host genomes and identifying misassembled metagenomic contigs.
Topics: Animals; Bacteria; DNA Methylation; DNA, Bacterial; Gastrointestinal Microbiome; Genome, Bacterial; Metagenome; Metagenomics; Mice; Nanopore Sequencing
PubMed: 33820988
DOI: 10.1038/s41592-021-01109-3 -
Cell Reports Oct 2018The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and...
The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci. Most silenced and enhanced genes coalesced in specific pathways including apoptosis, DNA repair, and cell metabolism. Cancer-germline antigens (CG) were frequently epigenomically enhanced and their expression correlated with response to anti-PD-1, but not anti-CTLA4, in skin melanoma. Finally, we demonstrated the potential of our approach to explore DNA methylation changes in pediatric tumors, which frequently lack genetic drivers and exhibit epigenomic modifications. Our results provide a pan-cancer map of aberrant DNA methylation to inform functional and therapeutic studies.
Topics: Cell Line, Tumor; Child; DNA Methylation; Epigenesis, Genetic; Gene Silencing; Humans; Neoplasms
PubMed: 30355485
DOI: 10.1016/j.celrep.2018.09.082 -
Small Methods Mar 2022DNA methylation is associated with transcriptional repression, genomic imprinting, stem cell differentiation, embryonic development, and inflammation. Aberrant DNA... (Review)
Review
Analysis and Performance Assessment of the Whole Genome Bisulfite Sequencing Data Workflow: Currently Available Tools and a Practical Guide to Advance DNA Methylation Studies.
DNA methylation is associated with transcriptional repression, genomic imprinting, stem cell differentiation, embryonic development, and inflammation. Aberrant DNA methylation can indicate disease states, including cancer and neurological disorders. Therefore, the prevalence and location of 5-methylcytosine in the human genome is a topic of interest. Whole-genome bisulfite sequencing (WGBS) is a high-throughput method for analyzing DNA methylation. This technique involves library preparation, alignment, and quality control. Advancements in epigenetic technology have led to an increase in DNA methylation studies. This review compares the detailed experimental methodology of WGBS using accessible and up-to-date analysis tools. Practical codes for WGBS data processing are included as a general guide to assist progress in DNA methylation studies through a comprehensive case study.
Topics: CpG Islands; DNA Methylation; Humans; Sulfites; Workflow
PubMed: 35064762
DOI: 10.1002/smtd.202101251 -
Biomedicine & Pharmacotherapy =... Jan 2020Quercetin is a kind of flavonoid compounds that comes from nature and is widely existed in the daily diet. Previous studies have found that quercetin has many effects... (Review)
Review
Quercetin is a kind of flavonoid compounds that comes from nature and is widely existed in the daily diet. Previous studies have found that quercetin has many effects such as anti-inflammatory, anti-oxidation and anti-cancer. Both in vivo and in vitro experiments have demonstrated that quercetin can exert anti-tumor effects by altering cell cycle progression, inhibiting cell proliferation, promoting apoptosis, inhibiting angiogenesis and metastasis progression, and affecting autophagy. This review summarizes the evidence for the pharmacological potential and inhibition of quercetin on cancers, supporting the viewpoint that quercetin should be adequately considered as a therapeutic agent against various cancers.
Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Humans; Neoplasms; Quercetin
PubMed: 31733570
DOI: 10.1016/j.biopha.2019.109604 -
Advanced Science (Weinheim,... Jul 2023While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms...
While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non-alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high-fat diet (HFD)-fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta-klotho (Klb), a co-receptor for the biological functions of fibroblast growth factor (FGF)15/19 and FGF21. DNA methyltransferases (DNMT) 1 and 3A mediate HFD-induced methylation at the Klb promoter. Notably, HFD enhances DNMT1 protein stability via a ubiquitination-mediated mechanism. Liver-specific deletion of Dnmt1 or 3a increases Klb expression and ameliorates HFD-induced hepatic steatosis. Single-nucleus RNA sequencing analysis reveals pathways involved in fatty acid oxidation in Dnmt1-deficient hepatocytes. Targeted demethylation at the Klb promoter increases Klb expression and fatty acid oxidation, resulting in decreased hepatic lipid accumulation. Up-regulation of methyltransferases by HFD may induce hypermethylation of the Klb promoter and subsequent down-regulation of Klb expression, resulting in the development of hepatic steatosis.
Topics: Mice; Animals; Lipid Metabolism; DNA Methylation; Epigenesis, Genetic; Fatty Liver; Fatty Acids
PubMed: 37282749
DOI: 10.1002/advs.202206068 -
Neurochemistry International Jul 2021Substance use disorders are complex biopsychosocial disorders that have substantial negative neurocognitive impact in various patient populations. These diseases involve... (Review)
Review
Substance use disorders are complex biopsychosocial disorders that have substantial negative neurocognitive impact in various patient populations. These diseases involve the compulsive use of licit or illicit substances despite adverse medicolegal consequences and appear to be secondary to long-lasting epigenetic and transcriptional adaptations in brain reward and non-reward circuits. The accumulated evidence supports the notion that repeated drug use causes changes in post-translational histone modifications and in DNA methylation/hydroxymethylation processes in several brain regions. This review provides an overview of epigenetic changes reported in models of cocaine, methamphetamine, and opioid use disorders. The accumulated data suggest that future therapeutic interventions should focus on the development of epigenetic drugs against addictive diseases.
Topics: Animals; Behavior, Addictive; Central Nervous System Stimulants; DNA Methylation; Epigenesis, Genetic; Humans; Reward; Substance-Related Disorders
PubMed: 33992741
DOI: 10.1016/j.neuint.2021.105069 -
Aging Nov 2021The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging...
Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test.
The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.
Topics: Adult; Aged; Aging; DNA Methylation; Dietary Supplements; Female; Geroscience; Humans; Ketoglutaric Acids; Male; Middle Aged; Vitamins
PubMed: 34847066
DOI: 10.18632/aging.203736