Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans ...and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the ...epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease.
We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes.
Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy.
This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite the success of genome-wide association studies (GWASs) in identifying loci associated with common diseases, a substantial proportion of the causality remains unexplained. Recent advances in ...genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, specifically variation in DNA methylation. Such epigenome-wide association studies (EWASs) present novel opportunities but also create new challenges that are not encountered in GWASs. We discuss EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies. We also discuss how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
DNA methylation plays a critical role in genome function both in health and disease. Almost 60 years after the discovery of 5-methyl cytosine and ∼25 years since the discovery that altered DNA ...methylation plays a role in disease, the first high-resolution DNA methylation profile (or methylome) of any genome – Arabidopsis thaliana – was determined. Although only ∼20% of the typical size of mammalian genomes, this milestone demonstrated that the methylomes of the human and similarly large genomes are now within reach. Here, we review current and emerging technologies that hold promise to deliver the first mammalian methylome and to facilitate comprehensive profiling of essentially any cell type in the context of development, disease and the environment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Identifying loci with parental differences in DNA methylation is key to unraveling parent-of-origin phenotypes. By conducting a MeDIP-Seq screen in maternal-methylation free postimplantation mouse ...embryos (Dnmt3L-/+), we demonstrate that maternal-specific methylation exists very scarcely at midgestation. We reveal two forms of oocyte-specific methylation inheritance: limited to preimplantation, or with longer duration, i.e. maternally imprinted loci. Transient and imprinted maternal germline DMRs (gDMRs) are indistinguishable in gametes and preimplantation embryos, however, de novo methylation of paternal alleles at implantation delineates their fates and acts as a major leveling factor of parent-inherited differences. We characterize two new imprinted gDMRs, at the Cdh15 and AK008011 loci, with tissue-specific imprinting loss, again by paternal methylation gain. Protection against demethylation after fertilization has been emphasized as instrumental in maintaining parent-of-origin methylation inherited from the gametes. Here we provide evidence that protection against de novo methylation acts as an equal major pivot, at implantation and throughout life.
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► Lifelong maintenance of parent-specific methylation marks is rare in mammals ► De novo methylation acts as a major leveling factor of parent-inherited differences ► Imprinted methylation marks can exist in a tissue-specific manner ► It is very likely that very few new imprinted loci remain to be discovered
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has ...constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including
) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.
Exposure of a developing foetus to maternal gestational diabetes (GDM) has been shown to programme future risk of diabetes and obesity. Epigenetic variation in foetal tissue may have a mechanistic ...role in metabolic disease programming through interaction of the pregnancy environment with gene function. We aimed to identify genome-wide DNA methylation variation in cord blood and placenta from offspring born to mothers with and without GDM. Pregnant women of South Asian origin were studied and foetal tissues sampled at term delivery. The Illumina HumanMethylation450 BeadChip was used to assay genome-wide DNA methylation in placenta and cord blood from 27 GDM exposed and 21 unexposed offspring. We identified 1485 cord blood and 1708 placenta methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value <0.05) with methylation differences of >5%. MVPs were disproportionately located within first exons. A bioinformatic co-methylation algorithm was used to detect consistent directionality of methylation in 1000 bp window around each MVP was observed at 74% of placenta and 59% of cord blood MVPs. KEGG pathway analysis showed enrichment of pathways involved in endocytosis, MAPK signalling and extracellular triggers to intracellular metabolic processes. Replication studies should integrate genomics and transcriptomics with longitudinal sampling to elucidate stability, determine causality for translation into biomarker and prevention studies.
Variation in cancer risk among somatic tissues has been attributed to variations in the underlying rate of stem cell division. For a given tissue type, variable cancer risk between individuals is ...thought to be influenced by extrinsic factors which modulate this rate of stem cell division. To date, no molecular mitotic clock has been developed to approximate the number of stem cell divisions in a tissue of an individual and which is correlated with cancer risk.
Here, we integrate mathematical modeling with prior biological knowledge to construct a DNA methylation-based age-correlative model which approximates a mitotic clock in both normal and cancer tissue. By focusing on promoter CpG sites that localize to Polycomb group target genes that are unmethylated in 11 different fetal tissue types, we show that increases in DNA methylation at these sites defines a tick rate which correlates with the estimated rate of stem cell division in normal tissues. Using matched DNA methylation and RNA-seq data, we further show that it correlates with an expression-based mitotic index in cancer tissue. We demonstrate that this mitotic-like clock is universally accelerated in cancer, including pre-cancerous lesions, and that it is also accelerated in normal epithelial cells exposed to a major carcinogen.
Unlike other epigenetic and mutational clocks or the telomere clock, the epigenetic clock proposed here provides a concrete example of a mitotic-like clock which is universally accelerated in cancer and precancerous lesions.
Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. ...Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here, we report the first genome-scale study of epigenomic dynamics during normal human aging. ...We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4(+) T-cells and CD14(+) monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ layer compared with blood, demonstrates that the aDMR signature is a multitissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture.
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