This modification can be inherited through cell division. Intraindividual changes in dna methylation not mediated by. 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. Koch cm, suschek cv, lin q, bork s, goergens m 2011 specific ageassociated dna methylation changes in human dermal fibroblasts. By comparing the genomewide methylation and expression patterns in different. 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. 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.
In 20, horvath developed an age predictor which can predict the biological age of a person across multiple tissues and cell types. I found that dna methylation age has the following properties. Measuring celltype specific differential methylation in. Role of dna methylation in human age prediction sciencedirect. 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. 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. Dna methylation age of human tissues and cell types steve horvath 1,2,3 abstract background. A the expression of dnase1l3 in human tissues and cell types. Recently, mtdna has been shown to have some covalent modifications such as methylation or hydroxylmethylation, which play pivotal epigenetic roles in mtdna replication. Progress in the study of genomic dna methylation led to the precise identification of methylation sites reflecting biological age of cells and tissues.
May, 2015 this corrects the article dna methylation age of human tissues and cell types in volume 14 on page r115. Tissue specific differential methylation has also been well characterized. If you use the r function in your published work, please cite it as follows. We collected dna methylation data from nine healthy human tissues from the.
We sought to extend these studies to create a map of differential dna methylation between different cell types derived from a single tissue. Using dna methylation profiling to evaluate biological age. Physical activity and global genomic dna methylation in a cancerfree population. Dna methylation age of human tissues and cell types. Dna methylation age of human tissues and cell types vol 14. Jeanpierre issa on dna methylation changes in aging cells and tissues, part of a collection of online lectures. 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.
Targeted and genomescale strategies reveal genebody. 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. Methylation status and human age at three autosomal loci. I developed a multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types. 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. Differences in dna methylation between human neuronal and. 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. Cureus effect of dna methylation in various diseases and. Normal breast, dna methylation, aging, 5mc, risk factors, reference free. Forensic application of dna methylation in ageprediction. Nuclear and mitochondrial dna methylation patterns induced. It also highlighted the aging process components and explained the role of dna methylation in age related diseases hannum et al. Vidal e, sayols s, moran s, guillaumetadkins a, schroeder mp, royo r, et al. A multitissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types has been developed.
Tissuespecific methylation patterns and expression of the human. 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. Dna methylation is predominantly restricted to cpgs, which are unevenly distributed across the genome. 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. Frontiers mitoepigenetics and its emerging roles in. Dna methylation age of human tissues and cell types vol. Mad values of more than 10 years, was observed in breast tissue, uterine endometrium, dermal. Predicting dna methylation level across human tissues.
Dna methylation is highly variable between individuals but also between cell types and tissues 4. 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. 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. By comparing the genomewide methylation and expression. Variation in dna methylation is also implicated in the development of diseases such as cancer 5, autoimmunity 6, and obesity 7. Intraindividual changes in dna methylation not mediated. Mitochondrial dna methylation is a phenomenon that is receiving everincreasing interest, particularly in diseases characterized by mitochondrial dysfunction. 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.
A across all cancer data sets, there is only a weak correlation cor0. 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. Dna methylation is a biochemical process that is important for normal development in higher organisms. 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. Mitochondrial genomic backgrounds affect nuclear dna. 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. The predictor, which is freely available, was developed using 8,000 samples from 82 illumina dna methylation. Cpg methylation patterns of human mitochondrial dna.
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. Horvath s 20 dna methylation age of human tissues and cell types. Here, we explore two possible dna methylation regulatory mechanisms with opposite modes of gene expression regulation. Many of these lesions cause structural damage to the dna molecule. 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. Through epigenetic mechanisms cells integrate environmental stimuli to finetune gene expression levels. Age acceleration in colorectal cancer, gbm and aml. Dna methylation dynamicsof humanhematopoietic stem cell. The authors estimated that the rate of formation of 8ohdg in brain tissue is more than tripled in old mice compared to young mice. Results i developed a multi tissue predictor of age that allows one to estimate the dna methylation age of most tissues and cell types. Nov 18, 20 dna methylation is a key epigenetic modification which, in mammals, occurs mainly at cpg dinucleotides. 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. However, the mechanism of dna methylation dependent gene regulation is not fully understood. Points are colored and labelled according to the underlying cancer data sets as described in additional file 1.
It is likely, then, that there may exist specific sites within a tissue that more accurately predict chrono logical age for that tissue. Notes on the role of dynamic dna methylation in mammalian. Lower heatmap is the analog for top 1500 cugps, ranked according to hypermethylation in breast. 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. Dna methylation age of human tissues and cell types steve horvath1,2 i recently described an epigenetic biomarker of aging. Both genes have very cpgpoor promoters, and methylation analysis by pairedend sequencing shows that a substantial number of cells from. Comparison of methods for quantification of global dna. Mitochondria and epigenetics trends in cell biology. 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. Dna repair is a collection of processes by which a cell identifies and corrects damage to the dna molecules that encode its genome. 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.
Dna methylation plays an important role in regulating gene expression during many biological processes. The role of dna methylation in type 1 and 2 diabetes as. 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. Regional differences in mitochondrial dna methylation in. However, the functional significance of mitochondrial dna mtdna methylation remains unknown.
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. Dec 12, 2015 dna methylation is a key epigenetic process involved in the regulation of nuclear gene expression. 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. Nuclear and mitochondrial dna methylation patterns induced by. Dna methylation age of human tissues and cell types genome.
We describe a blood test for detection of cell death in specific tissues based on two principles. Therefore, primary human hepatocytes phhs were exposed to an incubation concentration of vpa that was shown to cause steatosis without inducing overt cytotoxicity. Attesting to the evolutionary importance of dna methylation, these results could be later extended to mammals. Digestion of chromatin in apoptotic cell microparticles. 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. Variable dna methylation can be determined by cell differentiation. While all cancer tissues exhibit signs of severe age acceleration, this is not necessarily the case for individual cancer cell lines. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. Global dna hypomethylation, which is a common feature of several conditions such as ageing and cancer, can cause the undesirable activation of dormant repeat. Mitochondrial dna mtdna mutations and polymorphisms contribute to many complex diseases, including cancer. Dna methylation and complex human disease 1st edition. Tissuespecific methylation patterns and expression of the.
Dna methylation is a key epigenetic modification which, in mammals, occurs mainly at cpg dinucleotides. 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. 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. Tissueindependent and tissuespecific patterns of dna. 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. Development of tissuespecific age predictors using dna. Dna methylationbased age prediction from various tissues. I recently described an epigenetic biomarker of aging based on dna methylation dnam levels 1. Dna methylation changes in aging cells and tissues hstalks. Characterization of tissuespecific differential 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. 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. In addition, the gene was analyzed also in liver and intestinederived human cell lines hepg2 and caco2, respectively.
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. It also highlighted the aging process components and explained the role of dna methylation in agerelated diseases hannum et al. However, the mechanism of dnamethylationdependent gene regulation is not fully understood. 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. 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. Global dna hypomethylation, which is a common feature of several conditions such as ageing and cancer, can cause the undesirable activation of. Zhang ff, cardarelli r, carroll j, zhang s, fulda kg, gonzalez k, vishwanatha jk, morabia a, santella rm.
Based on ageassociated dna methylation changes that. We have identified tissuespecific dna methylation markers and developed a method for sensitive detection of these markers in plasma or serum. Dna methylationbased age prediction from various tissues and. This corrects the article dna methylation age of human tissues and cell types in volume 14 on page r115. 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. Each point corresponds to a dna methylation sample cancer sample from a human subject. In mouse and hamster cell lines, mtdna was found to be significantly less methylated than ndna with respect to 5methylcytosine 5 mc, and. Dna methylation plays a role in a variety of biological processes including embryonic development, imprinting, xchromosome inactivation, and stem cell differentiation.
Dna methylation, mitochondria, and programmed aging. Normal breast tissue dna methylation differences at regulatory. Valproic acid vpa is one of the most widely prescribed antiepileptic drugs in the world. Current understanding of dna methylation and agerelated.
Current understanding of dna methylation and agerelated disease. However, there are considerable differences in the amounts and distribution of dna methylation among different vertebrate tissues because dna. Wed like to understand how you use our websites in order to improve them. Most of the cpg methylation in the genome is found in repetitive regions, rich in dormant transposons and endogenous retroviruses. May, 2015 my conclusion section remains largely unchanged. However, the interesting part of the study was that the data showed significant differences in methylation age from several tissues.