Current understanding of dna methylation and agerelated disease. Most of the cpg methylation in the genome is found in repetitive regions, rich in dormant transposons and endogenous retroviruses. Valproic acid vpa is one of the most widely prescribed antiepileptic drugs in the world. Here, we explore two possible dna methylation regulatory mechanisms with opposite modes of gene expression regulation. Development of tissuespecific age predictors using dna. Celltype specific dna methylation patterns define human. Characterization of tissuespecific differential dna. In 20, horvath developed an age predictor which can predict the biological age of a person across multiple tissues and cell types. Tissuespecific methylation patterns and expression of the. Nov 05, 20 a multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types has been developed. Dna methylation plays a role in a variety of biological processes including embryonic development, imprinting, xchromosome inactivation, and stem cell differentiation. In humans and other mammals, dna methylation levels can be used to accurately estimate the age of tissues and cell types, forming an accurate epigenetic clock. Mitochondria and epigenetics trends in cell biology. Dec 12, 2015 dna methylation is a key epigenetic process involved in the regulation of nuclear gene expression.
This article has been cited by other articles in pmc. We developed a method of detecting tissuespecific cell death in humans based on tissuespecific methylation patterns in cfdna. In mouse and hamster cell lines, mtdna was found to be significantly less methylated than ndna with respect to 5methylcytosine 5 mc, and. However, existing methods rely on differences in dna sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. May, 2015 my conclusion section remains largely unchanged. Dna methylation, mitochondria, and programmed aging. Measuring celltype specific differential methylation in human brain tissue carolina m montano1,2, rafael a irizarry3, walter e kaufmann4, konrad talbot5, raquel e gur5, andrew p feinberg6 and margaret a taub7 abstract the behavior of epigenetic mechanisms in the brain is obscured by tissue heterogeneity and diseaserelated histological changes. Measuring celltype specific differential methylation in. Dna methylation age of human tissues and cell types genome. Cpg methylation patterns of human mitochondrial dna.
Zhang ff, cardarelli r, carroll j, zhang s, fulda kg, gonzalez k, vishwanatha jk, morabia a, santella rm. Current understanding of dna methylation and agerelated. However, the mechanism of dna methylation dependent gene regulation is not fully understood. Jeanpierre issa on dna methylation changes in aging cells and tissues, part of a collection of online lectures. Their epigenetic clock can estimate the biological age of various mouse models and can be applied to evaluate the effects of genetic, pharmacological, and dietary interventions on average lifespan. While all cancer tissues exhibit signs of severe age acceleration, this is not necessarily the case for individual cancer cell lines. The mitochondrial genome has long been implicated in agerelated disease, but no studies have examined its role in the relationship of longterm fine particle pm2. May, 2015 this corrects the article dna methylation age of human tissues and cell types in volume 14 on page r115.
Mitochondrial function is essential to provide the intermediate metabolites necessary to generate and modify epigenetic marks in the nucleus, which in turn can regulate the expression of mitochondrial proteins. However, there are considerable differences in the amounts and distribution of dna methylation among different vertebrate tissues because dna. A dna methylation map of human cancer at single basepair resolution. It turns out that cancer types are similar to individual cancer cell lines. Wed like to understand how you use our websites in order to improve them. The predictor, which is freely available, was developed using 8,000 samples from 82 illumina dna methylation. Global dna hypomethylation, which is a common feature of several conditions such as ageing and cancer, can cause the undesirable activation of dormant repeat. The mitochondrial genome has long been implicated in age related disease, but no studies have examined its role in the relationship of longterm fine particle pm2. Dna methylation age of human tissues and cell types steve horvath1,2 i recently described an epigenetic biomarker of aging. Cureus effect of dna methylation in various diseases and. Digestion of chromatin in apoptotic cell microparticles. Therefore, primary human hepatocytes phhs were exposed to an incubation concentration of vpa that was shown to cause steatosis without inducing overt cytotoxicity.
Based on ageassociated dna methylation changes that. Dna methylation is a key epigenetic process involved in the regulation of nuclear gene expression. Through epigenetic mechanisms cells integrate environmental stimuli to finetune gene expression levels. Nuclear and mitochondrial dna methylation patterns induced. Variable dna methylation can be determined by cell differentiation. Charting the dna methylation landscape of human hematopoietic differentiation a conceptual outline of human hematopoietic differentiation, highlighting the 17 hematopoietic cell types whose genomewide dna methylation patterns were pro.
A the expression of dnase1l3 in human tissues and cell types. Nuclear and mitochondrial dna methylation patterns induced by. Dna methylation age of human tissues and cell types vol. Dna methylation is a biochemical process that is important for normal development in higher organisms.
In human cells, both normal metabolic activities and environmental factors such as radiation can cause dna damage, resulting in as many as 1 million individual molecular lesions per cell per day. Dna methylationbased age prediction from various tissues. Using a unique mouse model that contains ndna from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strainsdesignated mitochondrial nuclear exchange mnxwe showed that mtdna could alter mammary tumor metastasis. Dna methylation plays an important role in regulating gene expression during many biological processes. There is substantial crosstalk between dna methylation and the polycomb mark. Intraindividual changes in dna methylation not mediated. Predicting dna methylation level across human tissues. Physical activity and global genomic dna methylation in a cancerfree population. Dna methylation changes in aging cells and tissues hstalks. However, in contrast to studies in cell lines or whole brain tissues, a direct comparison between dna methylation and rna expression within separate cell populations obtained from the human postmortem brain is not currently feasible because nucleisorting protocols are not compatible with preserving highquality rna that is required for gene. We sought to extend these studies to create a map of differential dna methylation between different cell types derived from a single tissue. I recently described an epigenetic biomarker of aging based on dna methylation dnam levels 1. Forensic application of dna methylation in ageprediction.
Normal breast, dna methylation, aging, 5mc, risk factors, reference free. Dna methylation age of human tissues and cell types. It is likely, then, that there may exist specific sites within a tissue that more accurately predict chrono logical age for that tissue. Progress in the study of genomic dna methylation led to the precise identification of methylation sites reflecting biological age of cells and tissues. Dna methylation is a key epigenetic modification which, in mammals, occurs mainly at cpg dinucleotides. Differences in dna methylation between human neuronal and. A multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types has been developed. Jan 31, 2015 one study, investigating genomewide dna methylation changes by comparing c57bl6 mice at 3 months of age to mice at 35 months of age, found that polycomb target genes and various tumor suppressor genes were enriched among the age dependently hypermethylated genes. This corrects the article dna methylation age of human tissues and cell types in volume 14 on page r115. Dna repair is a collection of processes by which a cell identifies and corrects damage to the dna molecules that encode its genome. If you use the r function in your published work, please cite it as follows. In the independent data set of six individuals and 24 lcl t cell pairs, the correlation r 2 between predicted value and t cell methylation was 0. Pdf it is not yet known whether dna methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types. Dna methylation dynamicsof humanhematopoietic stem cell.
However, the functional significance of mitochondrial dna mtdna methylation remains unknown. We describe a blood test for detection of cell death in specific tissues based on two principles. The most widely used method for epigenomewide analysis of dna methylation is the illumina 450k methylation array, and a number of studies have recently shown differential dna methylation of the nuclear genome ncdna, between different tissue types 1012 and also in a range of complex diseases, from brain disorders such as alzheimers. A across all cancer data sets, there is only a weak correlation cor0. Role of dna methylation in human age prediction sciencedirect. I found that dna methylation age has the following properties.
The most widely characterized dna methylation process is the covalent addition of the methyl group at the 5carbon of the cytosine ring resulting in 5. Dna methylation is highly variable between individuals but also between cell types and tissues 4. Age acceleration in colorectal cancer, gbm and aml. Targeted and genomescale strategies reveal genebody. Koch cm, suschek cv, lin q, bork s, goergens m 2011 specific ageassociated dna methylation changes in human dermal fibroblasts. Dna methylation is an important epigenetic mechanism involved in gene regulation, with alterations in dna methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial dna mtdna mutations and polymorphisms contribute to many complex diseases, including cancer. The role of dna methylation in type 1 and 2 diabetes as. By comparing the genomewide methylation and expression. Request pdf on may, 2015, steve horvath and others published dna methylation age of human tissues and cell types vol 14, pg r115, 20 find, read and cite all the research you need on. This modification can be inherited through cell division.
The authors estimated that the rate of formation of 8ohdg in brain tissue is more than tripled in old mice compared to young mice. Tissuespecific methylation patterns and expression of the human. Mitochondrial dna methylation is a phenomenon that is receiving everincreasing interest, particularly in diseases characterized by mitochondrial dysfunction. However, the interesting part of the study was that the data showed significant differences in methylation age from several tissues. We collected dna methylation data from nine healthy human tissues from the. Dna methylation age of human tissues and cell types vol 14.
Many of these lesions cause structural damage to the dna molecule. Global dna hypomethylation, which is a common feature of several conditions such as ageing and cancer, can cause the undesirable activation of. Vidal e, sayols s, moran s, guillaumetadkins a, schroeder mp, royo r, et al. It is not yet known whether dna methylation level s can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulti ng age prediction is a biologically meaningful measure. Comparison of methods for quantification of global dna. Dna methylation is an epigenetic mechanism that occurs by the addition of a methyl ch 3 group to dna, thereby often modifying the function of the genes and affecting gene expression. Frontiers mitoepigenetics and its emerging roles in. Notes on the role of dynamic dna methylation in mammalian.
I developed a multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types. Both genes have very cpgpoor promoters, and methylation analysis by pairedend sequencing shows that a substantial number of cells from. Tissue specific differential methylation has also been well characterized. Intraindividual changes in dna methylation not mediated by.
Choudry,4,5 peter ebert,2,3 johanna klughammer,1 samantha farrow,4,5 antonella santoro, 6valerio ciaurro, anthony mathur,7 rakesh uppal,7 hendrik g. Dna methylationbased age prediction from various tissues and. By comparing the genomewide methylation and expression patterns in different. Dna methylation and complex human disease 1st edition. Mad values of more than 10 years, was observed in breast tissue, uterine endometrium, dermal. Lower heatmap is the analog for top 1500 cugps, ranked according to hypermethylation in breast. Mitochondrial genomic backgrounds affect nuclear dna. Mar 21, 2016 in mouse and hamster cell lines, mtdna was found to be significantly less methylated than ndna with respect to 5methylcytosine 5 mc, and the level of 5 mc in mtdna as compared with that in. The aim of this study is to further investigate vpainduced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear dna ndna and mitochondrial dna mtdna. By comparing what is currently known of local and global changes, we hope to clarify the governing principles of dna methylation in mammalian development and set these roles in the context of the larger canon of epigenetic regulation.
Regional differences in mitochondrial dna methylation in. In addition, the gene was analyzed also in liver and intestinederived human cell lines hepg2 and caco2, respectively. However, the mechanism of dnamethylationdependent gene regulation is not fully understood. Attesting to the evolutionary importance of dna methylation, these results could be later extended to mammals. Using dna methylation profiling to evaluate biological age. Recently, mtdna has been shown to have some covalent modifications such as methylation or hydroxylmethylation, which play pivotal epigenetic roles in mtdna replication. Tissueindependent and tissuespecific patterns of dna. It also highlighted the aging process components and explained the role of dna methylation in agerelated diseases hannum et al.
Each point corresponds to a dna methylation sample cancer sample from a human subject. Nov 18, 20 dna methylation is a key epigenetic modification which, in mammals, occurs mainly at cpg dinucleotides. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. This builds on growing evidence for genebody methylation in mammals9,10,22 and shows it to be a general feature of all highly expressed genes in human cell lines.
We have identified tissuespecific dna methylation markers and developed a method for sensitive detection of these markers in plasma or serum. The earliest studies, which related dna methylation changes to the aging process, were investigating different organs and life stages of humpback salmon and found that 5methylcytosine 5mc levels during ontogenesis were significantly decreasing. A the nanog and oct4 pluripotency genes have been reported to be regulated by reversible dna methylation of their promoters and to be completely methylated in nonexpressing tissues. Dna methylation is predominantly restricted to cpgs, which are unevenly distributed across the genome. It is not yet known whether dna methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. The predictor, which is freely available, was developed using 8,000 samples from 82 illumina dna methylation array datasets, encompassing 51 healthy tissues and cell types. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring cytosine and adenine are two of the four bases of dna. Normal breast tissue dna methylation differences at regulatory. Horvath s 20 dna methylation age of human tissues and cell types.
Dna methylation age of human tissues and cell types steve horvath 1,2,3 abstract background. Points are colored and labelled according to the underlying cancer data sets as described in additional file 1. Methylation status and human age at three autosomal loci. It also highlighted the aging process components and explained the role of dna methylation in age related diseases hannum et al. Results i developed a multi tissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types. Horvath developed a multitissue predictor of age using 8000 samples from 82 illumina dna methylation array datasets, encompassing 51 healthy tissues and cell types 89, 90. Oct 21, 20 i developed a multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types. Cell stem cell resource dna methylation dynamics of human hematopoietic stem cell differentiation matthias farlik,1, florian halbritter,1, fabian muller, 2,3, fizzah a. We found that our method can greatly improve accuracy of crosstissue prediction at cpg sites that are variable in the target tissue r2 increases from 0. Variation in dna methylation is also implicated in the development of diseases such as cancer 5, autoimmunity 6, and obesity 7.
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