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Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.

A range of in utero and early-life factors can influence offspring epigenetics, particularly DNA methylation patterns. This study aimed to investigate the influence of a dietary intervention and factors in pregnancy on offspring epigenetic profile at five years of age. We also explored associations between body composition and methylation profile in a cross-sectional analysis. Sixty-three five-year-olds were selected from the ROLO Kids Study, a Randomized controlled trial Of a LOw glycemic index dietary intervention from the second trimester of pregnancy. DNA methylation was investigated in 780,501 CpG sites in DNA isolated from saliva. Principal component analysis identified no association between maternal age, weight, or body mass index (BMI) during pregnancy and offspring DNA methylation (p > 0.01). There was no association with the dietary intervention during pregnancy, however, gene pathway analysis identified functional clusters involved in insulin secretion and resistance that differed between the intervention and control. There were no associations with child weight or adiposity at five years of age; however, change in weight from six months was associated with variation in methylation. We identified no evidence of long-lasting influences of maternal diet or factors on DNA methylation at age five years. However, changes in child weight were associated with the methylome in childhood.

The pathogenesis of systemic lupus erythematosus (SLE) is influenced by both genetic factors and epigenetic modifications; the latter is a result of exposure to various environmental factors. Epigenetic modifications affect gene expression and alter cellular functions without modifying the genomic sequences. CpG-DNA methylation, histone modifications, and miRNAs are the main epigenetic factors of gene regulation. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur in CD4+ T-cells. Moreover, histone acetylation and deacetylation inhibitors reverse the expression of multiple genes involved in SLE, indicating histone modification in SLE. Autoreactive T-cells and B-cells have been shown to alter the patterns of epigenetic changes in SLE patients. Understanding the molecular mechanisms involved in the pathogenesis of SLE is critical for the introduction of effective, target-directed and tolerated therapies. In this review, we summarize the recent findings that highlight the importance of epigenetic modifications and their mechanisms in SLE.

Identifying and validating molecular targets of interventions that extend the human health span and lifespan has been difficult, as most clinical biomarkers are not sufficiently representative of the fundamental mechanisms of ageing to serve as their indicators. In a recent breakthrough, biomarkers of ageing based on DNA methylation data have enabled accurate age estimates for any tissue across the entire life course. These ‘epigenetic clocks’ link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course. Epigenetic biomarkers may help to address long-standing questions in many fields, including the central question: why do we age?

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging. People’s bodies age at different rates. Age-related biological changes that increase the risk of disease and disability progress rapidly in some people. In others, these processes occur at a slower pace, allowing those individuals to live longer, healthier lives. This observation has led scientists to try to develop therapies that slow aging. The hope is that such treatments could prevent or delay diseases like heart disease or dementia, for which older age is the leading risk factor. Studies in animals have identified treatments that extend the creatures’ lives and slow age-related disease. But testing these treatments in humans is challenging. Our lives are much longer than the worms, flies or mice used in the experiments. Scientists would have to follow human study participants for decades to detect delays in disease onset or an extension of their lives. An alternative approach is to try to develop a test that measures the pace of aging, or essentially “a speedometer for aging”. This would allow scientists to more quickly determine if treatments slow the aging process. Now, Belsky et al. show a blood test designed to measure the pace of aging predicts which people are at increased risk of poor health, chronic disease and an earlier death. First, data about chemical changes to an individual’s DNA, called DNA methylation, were analyzed from white blood cell samples collected from 954 people in a long-term health study known as “The Dunedin Study”. Using the data, Belsky et al. then developed an algorithm – named “DunedinPoAm” – that identified people with an accelerated or slowed pace of aging based on a single blood test. Next, they used the algorithm on samples from participants in three other long-term studies. This verified that those people the algorithm identified as aging faster had a greater risk of poor health, developing chronic diseases or dying earlier. Similarly, those identified as aging more slowly performed better on tests of balance, strength, walking speed and mental ability, and they also looked younger to trained raters. Additionally, Belsky et al. used the test on participants in a randomized trial testing whether restricting calories had potential to extend healthy lifespan. The results suggested that the calorie restriction could counter the effects of an accelerated pace of aging. The test developed by Belsky et al. may provide an alternate way of measuring whether age-slowing treatments work. This would allow faster testing of treatments that can extend the healthy lifespan of humans. The test may also help identify individuals with accelerated aging. This might help public health officials test whether policies or programs can help people lead longer, healthier lives.

Key Points DNA methylation is an epigenetic mark that can be mitotically inherited and is involved in adding stability to the repression of transcription when it is located at the start sites of mammalian genes. Our ability to obtain complete methylomes has transformed our appreciation of the role of DNA methylation in epigenetic processes. DNA methylation in the bodies of genes has long been ignored but might be involved in differential promoter usage and also in transcription elongation and alternative splicing. Repetitive DNA from intragenomic parasites is heavily methylated, which allows transcription of the host gene at the same time as preventing transcription initiation of the repetitive DNA. Methylation of control regions outside of the transcription start sites — such as enhancers and insulators — is increasingly being recognized as being functionally important. Demethylation of DNA is now accepted as being essential for embryonic development and seems to occur mainly in regions of DNA that are not CpG islands; thus, methylation patterns are increasingly being realized as being far more dynamic than previously recognized. Our understanding of the function of DNA methylation is developing now that we are able to look beyond CpG-rich regions at transcriptional start sites. The emerging picture is of a complex relationship between DNA methylation and transcription and of possible additional roles of methylation. DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

Key Points RNA-directed DNA methylation (RdDM) is prevalent in flowering plants and induces transcriptional silencing at repetitive DNA, including all types of transposons. During RdDM, RNA polymerase IV (Pol IV) initiates production of 24-nucleotide small interfering RNAs (siRNAs) that direct transcriptionally repressive DNA methylation to homologous Pol V-transcribed loci. Pol IV and Pol V are recruited to genomic regions that contain transcriptionally repressive epigenetic marks, thereby reinforcing and maintaining the silent state. Recent research has uncovered variations on the canonical RdDM pathway, including the involvement of RNA-DEPENDENT RNA POLYMERASE 6 (RDR6) and NEEDED FOR RDR2-INDEPENDENT DNA METHYLATION (NERD), which might allow 'young' (that is, recently acquired) transposons to come under the control of RdDM. In additional to transposon control, RdDM might help hosts to respond to biotic or abiotic challenges, or to faithfully transmit DNA methylation patterns to their offspring. RdDM might also affect germ cell specification and parent-specific gene expression. There is increasing evidence that siRNAs are used to communicate epigenetic states between homologous sequences within a nucleus or indeed between nuclei. RNA-directed DNA methylation (RdDM) is a major mechanism of transcriptional gene silencing in plants that is mediated through small interfering RNAs (siRNAs) and plant-specific RNA polymerases. This Review summarizes our latest understanding of RdDM, including its genomic targets, molecular mechanisms (such as emerging non-canonical pathways) and diverse biological roles. RNA-directed DNA methylation (RdDM) is the major small RNA-mediated epigenetic pathway in plants. RdDM requires a specialized transcriptional machinery that comprises two plant-specific RNA polymerases — Pol IV and Pol V — and a growing number of accessory proteins, the functions of which in the RdDM mechanism are only partially understood. Recent work has revealed variations in the canonical RdDM pathway and identified factors that recruit Pol IV and Pol V to specific target sequences. RdDM, which transcriptionally represses a subset of transposons and genes, is implicated in pathogen defence, stress responses and reproduction, as well as in interallelic and intercellular communication.

In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.

Mouse embryos acquire global DNA methylation of their genome during implantation. However the exact roles of DNA methyltransferases (DNMTs) in embryos have not been studied comprehensively. Here we systematically analyze the consequences of genetic inactivation of Dnmt1 , Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos. We find a strict division of function between DNMT1, responsible for maintenance methylation, and DNMT3A/B, solely responsible for methylation acquisition in development. By analyzing severely hypomethylated embryos, we uncover multiple functions of DNA methylation that is used as a mechanism of repression for a panel of genes including not only imprinted and germline genes, but also lineage-committed genes and 2-cell genes. DNA methylation also suppresses multiple retrotransposons and illegitimate transcripts from cryptic promoters in transposons and gene bodies. Our work provides a thorough analysis of the roles of DNA methyltransferases and the importance of DNA methylation for transcriptome integrity in mammalian embryos. DNA methyltrasferases play important role during mouse embryo development. Here the authors reveal the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos genome-wide.

The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX , DAXX , and MEN1 . We genotyped 64 PanNETs and found 58% carry ATRX , DAXX , and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q -value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. In pancreatic neuroendocrine tumors (PanNETs) ATRX, DAXX, and MEN1 are commonly mutated (A-D-M mutant PanNETs). Here, the authors find in a cohort of PanNETS 58% are A-D-M mutant PanNETs, with a worse clinical outcome and differences in gene expression and methylation compared to A-D-M wild type cases- these gene expression differences suggest that A-D-M mutant PanNETs potentially originate from a cell type similar to alpha cells.