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A large-scale epigenome-wide association study identifies changes in DNA methylation associated with body mass index in blood and adipose tissue, and correlates DNA methylation sites with high risk of incident type 2 diabetes. Body fat and diabetes risk Obesity is a major risk factor for type 2 diabetes and related metabolic disorders. Genetic association studies have identified genomic loci associated with obesity, and recent studies have also suggested associations with DNA methylation. These authors report an epigenome-wide association study for body mass index (BMI), identifying an association with DNA methylation at 187 loci in blood and adipose tissue. They find that these methylation changes are secondary to adiposity and are also associated with an increased risk of developing type 2 diabetes, independent of conventional risk factors. Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances 1 , 2 . Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation 3 , 4 , 5 , 6 , a key regulator of gene expression and molecular phenotype 7 . Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P  < 1 × 10 −7 , range P  = 9.2 × 10 −8 to 6.0 × 10 −46 ; n  = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues ( P  < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci ( P  < 9.0 × 10 −6 , range P  = 5.5 × 10 −6 to 6.1 × 10 −35 , n  = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P  = 1.1 × 10 −54 ). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m2, 16·7 mg/m2, 24·6 mg/m2, 33 mg/m2, 55 mg/m2, and 83 mg/m2) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m2 cohort, three patients in the 16·7 mg/m2 cohort, three patients in the 24·6 mg/m2 cohort, four patients in the 33 mg/m2 cohort, three patients in the 55 mg/m2, and six patients in the 83 mg/m2 cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m2. Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m2 was recommended as the targeted dose for phase 2 trials. EpicentRx (formerly RadioRx).

Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable ‘epimutations’ contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.In this Review, Fitz-James and Cavalli discuss the diverse and often multilayered mechanisms by which transgenerational epigenetic inheritance can occur in different species.

Specific chemical modifications of biological molecules are an efficient way of regulating molecular function, and a plethora of downstream signalling pathways are influenced by the modification of DNA and proteins. Many of the enzymes responsible for regulating protein and DNA modifications are targets of current cancer therapies. RNA epitranscriptomics, the study of RNA modifications, is the new frontier of this arena. Despite being known since the 1970s, eukaryotic RNA modifications were mostly identified on transfer RNA and ribosomal RNA until the last decade, when they have been identified and characterized on mRNA and various non-coding RNAs. Increasing evidence suggests that RNA modification pathways are also misregulated in human cancers and may be ideal targets of cancer therapy. In this Review we highlight the RNA epitranscriptomic pathways implicated in cancer, describing their biological functions and their connections to the disease.After synthesis, all RNA molecules are subject to covalent modifications. This Review presents the evidence that RNA modification pathways are misregulated in cancer and suggests that they may be ideal targets for cancer therapy.

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3′ UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene ( TERT ) paradoxically confer higher IEAA ( P  < 2.7 × 10 −11 ). Causal modeling indicates TERT -specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening. Epigenetic clocks based on DNA methylation levels are estimators of chronological age. Here, the authors perform a GWAS of epigenetic aging rates in blood and find SNP variants in the TERT locus associated with increased intrinsic epigenetic age are also associated with longer telomeres.

Epigenetic modifiers such as erasers, readers, writers, and recruiters control abiotic stress response in flowering plants.

The role of the stress-induced transcription factor ATF7 in immunity is largely unknown. Ishii and colleagues show that ATF7 represses select innate immunity–related genes, but activity is downregulated during the induction of macrophage memory. Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcription factor ATF7 in innate immunological memory. ATF7 suppressed a group of genes encoding factors involved in innate immunity in macrophages by recruiting the histone H3K9 dimethyltransferase G9a. Treatment with lipopolysaccharide, which mimics bacterial infection, induced phosphorylation of ATF7 via the kinase p38, which led to the release of ATF7 from chromatin and a decrease in repressive histone H3K9me2 marks. A partially disrupted chromatin structure and increased basal expression of target genes were maintained for long periods, which enhanced resistance to pathogens. ATF7 might therefore be important in controlling memory in cells of the innate immune system.

Kinetochores assemble on distinct ‘centrochromatin’ containing the histone H3 variant CENP‐A and interspersed nucleosomes dimethylated on H3K4 (H3K4me2). Little is known about how the chromatin environment at active centromeres governs centromeric structure and function. Here, we report that centrochromatin resembles K4–K36 domains found in the body of some actively transcribed housekeeping genes. By tethering the lysine‐specific demethylase 1 (LSD1), we specifically depleted H3K4me2, a modification thought to have a role in transcriptional memory, from the kinetochore of a synthetic human artificial chromosome (HAC). H3K4me2 depletion caused kinetochores to suffer a rapid loss of transcription of the underlying α‐satellite DNA and to no longer efficiently recruit HJURP, the CENP‐A chaperone. Kinetochores depleted of H3K4me2 remained functional in the short term, but were defective in incorporation of CENP‐A, and were gradually inactivated. Our data provide a functional link between the centromeric chromatin, α‐satellite transcription, maintenance of CENP‐A levels and kinetochore stability. Here, centromeric histone marks on a human artificial chromosome are found to resemble the chromatin landscape in transcribed genes, and selective manipulation shows them to govern the incorporation of the centromere‐specifying CENP‐A histone variant.

Key Points The histone code is regulated by epigenetic 'readers', 'writers' and 'erasers'. This Review proposes adding to this paradigm the availability of the 'ink' needed to pen chromatin modifications, with the ink being metabolites that are substrates of chromatin-modifying enzymes (that is, for example, acetyl-CoA is the ink for acetyltransferases). This Review puts forward a three-model framework by which metabolism can regulate the epigenome: inhibitor metabolite production; nutrient sensing and chromatin regulation; and localized metabolite production. Metabolic and epigenetic changes are both common features found in all cancer types. Metabolic rewiring in cancer cells provides advantages not only through direct metabolic functions, but also by acting on the epigenetic landscape. Cell signalling has long been known to affect nutrient uptake and use. However, metabolism also feeds back onto signalling pathways to play an active part in major cellular decisions, such as proliferation or differentiation. This reciprocal feedback between cell signalling and metabolism is manipulated in cancer cells to provide growth and survival advantages. Improved understanding of the interplay between cell metabolism and the epigenome will be crucial in designing novel cancer therapeutic strategies. Alterations in the epigenome and metabolism bidirectionally regulate molecular rewiring in cancer cells. This Review discusses how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis as well as therapeutic responses. Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription. We discuss how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis, as well as therapeutic responses.