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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.

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.

H2020 European Research Council, Grant/Award Number: ERC-2014-AdG/669622; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18061FERN; Ministerio de Ciencia e Innovación, Grant/Award Number: SAF2013-48256-R; the Asturias Regionla Government (PCTI) co-funding 2018- 2022/FEDER (IDI/2018/146), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527)...

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.

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.

Summary Cancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

This work was supported by: the Spanish Association Against Cancer (Grant number PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) cofounding 2018–2022/FEDER (Grant number IDI/2018/146 to M.F.F.), the Fundación General CSIC (Grant number 0348_CIE_6_E to M.F.F.), the Institute of Health Carlos III (Plan Nacional de I + D + I) cofounding FEDER (Grant numbers PI18/01527 and PI21/01067 to M.F.F. and A.F.F.; Grant numbers PI17/01517 and PI20/00269 to E.L.), and the Spanish Ministry of Science and Innovation (Grant number SGL2021-03-039/40 to M.F.F.) cofounding NextGenerationEU. J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation (Grant number IJC2018-36825-I). J.J.A.L. is supported by the Spanish Association Against Cancer (Grant number PRDAS21642ALBA). R.F.P. and D.B.R. are supported by the Severo Ochoa program (Grant numbers BP17-114 and BP20-186). We also acknowledge support from the Institute of Oncology of Asturias (IUOPA, supported by Obra Social Cajastur Liberbank, Spain), the Health Research Institute of Asturias (ISPA-FINBA), the Health Research Institute INCLIVA and the Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII).

We want to particularly acknowledge for its collaboration, the Principado de Asturias BioBank (PT17/0015/0023), financed jointly by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III, and Fundación Bancaria Cajastur and integrated with the Spanish National Biobanks Network. Plan Nacional de I + D + I/ISCIII grants PI16/00280 and PI19/00560 (J.M.G.-P.), and PI18/01527 (M.F.F. and A.F.F.); CIBERONC grant CB16/12/00390 (J.P.R.), and the FEDER Funding Program from the European Union. R.G.-D. is a recipient of a Severo Ochoa predoctoral fellowship from the Principado de Asturias (grant # BP19-063) (...)

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.