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Nutrients Mar 2019DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. However, aberrant DNA methylation, which is a nearly universal finding in... (Review)
Review
DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. However, aberrant DNA methylation, which is a nearly universal finding in cancer, can result in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers such as colon, stomach, cervical, prostate, and breast cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation either by directly inhibiting enzymes that catalyze DNA methylation or by changing the availability of substrates required for those enzymatic reactions such as the availability and utilization of methyl groups. In this review, we focused on nutrients that act as methyl donors or methylation co-factors and presented intriguing evidence for the role of these bioactive food components in altering DNA methylation patterns in cancer. Such a role is likely to have a mechanistic impact on the process of carcinogenesis and offer possible therapeutic potentials.
Topics: DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Micronutrients; Neoplasms; Nutritional Status
PubMed: 30871166
DOI: 10.3390/nu11030608 -
Nature Reviews. Clinical Oncology Jul 2018Changes in DNA methylation in cancer have been heralded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers. Despite... (Review)
Review
Changes in DNA methylation in cancer have been heralded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers. Despite the existence of more than 14,000 scientific publications describing DNA methylation-based biomarkers and their clinical associations in cancer, only 14 of these biomarkers have been translated into a commercially available clinical test. Methodological and experimental obstacles are both major causes of this disparity, but the genomic location of a DNA methylation-based biomarker is an intrinsic and essential property that also has an important and often overlooked role. Here, we examine the importance of the location of DNA methylation for the development of cancer biomarkers, and take a detailed look at the genomic location and other relevant characteristics of the various biomarkers with commercially available tests. We also emphasize the value of publicly available databases for the development of DNA methylation-based biomarkers and the importance of accurate reporting of the full methodological details of research findings.
Topics: Biomarkers, Tumor; DNA Methylation; Epigenesis, Genetic; Genome, Human; Humans; Neoplasms
PubMed: 29666440
DOI: 10.1038/s41571-018-0004-4 -
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 -
Annual Review of Medicine 2015Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of... (Review)
Review
Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.
Topics: Antineoplastic Agents; DNA Damage; DNA Methylation; DNA Repair; Humans; Neoplasms; Radiotherapy
PubMed: 25423595
DOI: 10.1146/annurev-med-081313-121208 -
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 -
Life Sciences Feb 2022Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer.... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer. Environmental and genetic predisposition are the two major etiological or risk factors involved in the pathology of the IPF. Among the environmental risk factors, smoking is one of the major causes for the development of IPF. Epigenetic pathways like nucleosomes remodeling, DNA methylation, histone modifications and miRNA mediated genes play a crucial role in development of IPF. Mutations in the genes make the epigenetic factors as important drug targets in IPF. Transcriptional changes due to environmental factors are also involved in the progression of IPF. The mutations in human telomerase reverse transcriptase (hTERT) have shown decreased life expectancy in IPF patients. The TERT-gene is highly expressed in chronic smokers and makes the role of epigenetics evident. Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and FibroGen-FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms. Thus, the study on epigenetics opens a wide window for the discovery of newer drugs. This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis
PubMed: 34998839
DOI: 10.1016/j.lfs.2021.120283 -
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 -
Current Topics in Behavioral... 2022Aggression is a complex behavioral trait modulated by both genetic and environmental influences on gene expression. By controlling gene expression in a reversible yet... (Review)
Review
Aggression is a complex behavioral trait modulated by both genetic and environmental influences on gene expression. By controlling gene expression in a reversible yet potentially lasting manner in response to environmental stimulation, epigenetic mechanisms represent prime candidates in explaining both individual differences in aggression and the development of elevated aggressive behaviors following life adversity. In this manuscript, we review the evidence for an epigenetic basis in the development and expression of aggression in both humans and related preclinical animal models. In particular, we discuss reports linking DNA methylation, histone post-translational modifications, as well as non-coding RNA, to the regulation of a variety of genes implicated in the neurobiology of aggression including neuropeptides, the serotoninergic and dopaminergic systems, and stress response related systems. While clinical reports do reveal interesting patterns of DNA methylation underlying individual differences and experience-induced aggressive behaviors, they do, in general, face the challenge of linking peripheral observations to central nervous system regulations. Preclinical studies, on the other hand, provide detailed mechanistic insights into the epigenetic reprogramming of gene expression following life adversities. Although the functional link to aggression remains unclear in most, these studies together do highlight the involvement of epigenetic events driven by DNA methylation, histone modifications, and non-coding RNA in the neuroadaptations underlying the development and expression of aggression.
Topics: Aggression; Animals; DNA Methylation; Epigenesis, Genetic; Histone Code; RNA, Untranslated
PubMed: 34595741
DOI: 10.1007/7854_2021_252 -
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