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Key Points Epigenetics is the study of variations in gene function (phenotypes) that are somatically heritable (and sometimes also from one generation to the next), but which are not caused by genetic alterations. In plants and animals, different epigenetic modifications, including DNA methylation, can have long-term effects on gene expression. The environment affects gene expression and phenotypes, both in plants and animals. Although it triggers natural developmental processes in some species, it often has deleterious effects that have consequences for development and disease. Different environmental cues (such as nutrition, chemical compounds, temperature changes and other stresses) can affect phenotypes and epigenetic gene regulation in experimental model systems. A growing number of human studies have demonstrated long-term effects as a consequence of diet, exposure to chemical components and other external factors. The effects are particularly apparent when exposure to the environmental factor occurs during gestation. For many environmentally induced phenotypes, particularly in humans, it remains unclear to what extent epigenetic modifications could be involved. This is a challenge for future research. Genetic differences between individuals influence epigenetic deregulation, and possibly also susceptibility to environmental stresses. There is considerable interest in exploring whether environmental factors, including chemicals and dietary components, can alter epigenomes. Environmentally induced changes in epigenetic marks are important in the development of several species, such as plants and insects; whether they influence human disease will be an area for future research. Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.

TERRAs are long non-coding RNAs generated from the telomeres. Lack of TERRA knockout models has hampered understanding TERRAs’ functions. We recently identified chromosome 20q as one of the main origins of human TERRAs, allowing us to generate the first 20q-TERRA knockout models and to demonstrate that TERRAs are essential for telomere length maintenance and protection. Here, we use ALT 20q-TERRA knockout cells to address a direct role of TERRAs in telomeric heterochromatin formation. We find that 20q-TERRAs are essential for the establishment of H3K9me3, H4K20me3, and H3K27me3 heterochromatin marks at telomeres. At the mechanistic level, we find that TERRAs bind to PRC2, responsible for catalyzing H3K27 tri-methylation, and that its localization to telomeres is TERRA-dependent. We further demonstrate that PRC2-dependent H3K27me3 at telomeres is required for the establishment of H3K9me3, H4K20me3, and HP1 binding at telomeres. Together, these findings demonstrate an important role for TERRAs in telomeric heterochromatin assembly. Long non-coding RNA TERRAs are essential for telomere protection and telomere length maintenance. Here the authors report a role for TERRAs in telomeric heterochromatin formation by recruiting Polycomb Repressive Complex 2 to telomeres.

Monozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins. Skeletal muscle (n = 11 pairs) and subcutaneous adipose tissue (n = 5 pairs) biopsies were collected from 53-80 year-old monozygotic twin pairs discordant for type 2 diabetes. DNA methylation was measured by microarrays at 26,850 cytosine-guanine dinucleotide (CpG) sites in the promoters of 14,279 genes. Bisulfite sequencing was applied to validate array data and to quantify methylation of intergenic repetitive DNA sequences. The overall intra-pair variation in DNA methylation was large in repetitive (LINE1, D4Z4 and NBL2) regions compared to gene promoters (standard deviation of intra-pair differences: 10% points vs. 4% points, P<0.001). Increased variation of LINE1 sequence methylation was associated with more phenotypic dissimilarity measured as body mass index (r = 0.77, P = 0.007) and 2-hour plasma glucose (r = 0.66, P = 0.03) whereas the variation in promoter methylation did not associate with phenotypic differences. Validated methylation changes were identified in the promoters of known type 2 diabetes-related genes, including PPARGC1A in muscle (13.9±6.2% vs. 9.0±4.5%, P = 0.03) and HNF4A in adipose tissue (75.2±3.8% vs. 70.5±3.7%, P<0.001) which had increased methylation in type 2 diabetic individuals. A hypothesis-free genome-wide exploration of differential methylation without correction for multiple testing identified 789 and 1,458 CpG sites in skeletal muscle and adipose tissue, respectively. These methylation changes only reached some percentage points, and few sites passed correction for multiple testing. Our study suggests that likely acquired DNA methylation changes in skeletal muscle or adipose tissue gene promoters are quantitatively small between type 2 diabetic and non-diabetic twins. The importance of methylation changes in candidate genes such as PPARGC1A and HNF4A should be examined further by replication in larger samples.

The emergence of nanotechnology applied to medicine has revolutionized the treatment of human cancer. As in the case of classic drugs for the treatment of cancer, epigenetic drugs have evolved in terms of their specificity and efficiency, especially because of the possibility of using more effective transport and delivery systems. The use of nanoparticles (NPs) in oncology management offers promising advantages in terms of the efficacy of cancer treatments, but it is still unclear how these NPs may be affecting the epigenome such that safe routine use is ensured. In this work, we summarize the importance of the epigenetic alterations identified in human cancer, which have led to the appearance of biomarkers or epigenetic drugs in precision medicine, and we describe the transport and release systems of the epigenetic drugs that have been developed to date.

Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1 + circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1 + crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1 + crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1 + crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1 + crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy. Glypican-1 identifies cancer exosomes and serves as a biomarker for detection of early pancreatic cancer in patients and mouse models of the disease; the findings may enable early and non-invasive identification, and prevention of malignant cancer. Exoxomes as an early test for cancer Most cells shed so-called extracellular vesicles or exosomes consisting of proteins and nucleic acids enclosed in phospholipid bilayers. Exosomes derived from cancer cells can be isolated from the blood circulation of cancer patients and carry tumour-derived material. Raghu Kalluri and colleagues now identify exosomes containing glypican-1 as a biomarker for early pancreatic cancer, in patients and in mouse models of the disease. These findings may enable non-invasive tests for the early detection of pancreatic cancers.

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. Aging and cancer are interrelated processes which share common epigenetic alterations. Nonetheless, there are differences in some of the DNA methylation changes which occur in both phenomena. The recent development of epigenetic clocks will help dissect the common and specific epigenetic characteristics of aging and cancer, although the mechanisms underlying epigenetic clocks are yet to be clarified, particularly in relation to somatic stem cell epigenetic aging.

Pluripotent stem cells (PSCs) transition between cell states in vitro, reflecting developmental changes in the early embryo. PSCs can be stabilized in the naive state by blocking extracellular differentiation stimuli, particularly FGF–MEK signalling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF–MEK signalling or global DNA methylation. Mechanistically, chemical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their ability to repress the Mediator complex at enhancers. CDK8/19 inhibition therefore increases Mediator-driven recruitment of RNA polymerase II (RNA Pol II) to promoters and enhancers. This efficiently stabilizes the naive transcriptional program and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with a reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be achieved in vitro by inhibiting CDK8/19 kinase activity. These principles may apply to other contexts of cellular plasticity.Lynch et al. demonstrate that inhibiting CDK8 and CDK19 kinases increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers, therefore stabilizing the naive transcriptional program.

The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum. A single cycle of transient OSKM activation in naturally aged mice is able to partially reverse age‐associated changes in several tissues. Specifically, we could capture reversion of alterations occurring with aging at the level of DNA methylation, transcription, as well as, serum metabolome. These changes were stable for a period of up to four weeks after OSKM cessation.

Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine—phosphate—guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.

Glioblastoma (GBM) is one of the most aggressive types of cancer and exhibits profound genetic and epigenetic heterogeneity, making the development of an effective treatment a major challenge. The recent incorporation of molecular features into the diagnosis of patients with GBM has led to an improved categorization into various tumour subtypes with different prognoses and disease management. In this work, we have exploited the benefits of genome‐wide multi‐omic approaches to identify potential molecular vulnerabilities existing in patients with GBM. Integration of gene expression and DNA methylation data from both bulk GBM and patient‐derived GBM stem cell lines has revealed the presence of major sources of GBM variability, pinpointing subtype‐specific tumour vulnerabilities amenable to pharmacological interventions. In this sense, inhibition of the AP‐1, SMAD3 and RUNX1/RUNX2 pathways, in combination or not with the chemotherapeutic agent temozolomide, led to the subtype‐specific impairment of tumour growth, particularly in the context of the aggressive, mesenchymal‐like subtype. These results emphasize the involvement of these molecular pathways in the development of GBM and have potential implications for the development of personalized therapeutic approaches.