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.
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Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has ...been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human ...epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.
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DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression, yet its ...function is unknown. We show that 5-aza-2′-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC. Downregulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may, therefore, be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene overexpression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription.
•Fast remethylation is often seen in the gene bodies of oncogenic regulated genes•Slowly remethylating loci are frequently located in promoters methylated in tumors•Rapid remethylation and restoration of expression levels require DNMT3B•There is a causal relationship between gene body DNA methylation and gene expression
Yang et al. show a causal relationship between DNA methylation at the gene body and gene expression; thus, the cancer therapeutic activity of DNA methylation inhibitors may be due to not only inducing the expression of aberrantly silenced genes but also to repressing the expression of aberrantly overexpressed genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multicellular eukaryotic genomes show enormous differences in size. A substantial part of this variation is due to the presence of transposable elements (TEs). They contribute significantly to a ...cell’s mass of DNA and have the potential to become involved in host gene control. We argue that the suppression of their activities by methylation of the C–phosphate–G (CpG) dinucleotide in DNA is essential for their long-term accommodation in the host genome and, therefore, to its expansion. An inevitable consequence of cytosine methylation is an increase in C-to-T transition mutations via deamination, which causes CpG loss. Cytosine deamination is often needed for TEs to take on regulatory functions in the host genome. Our study of the whole-genome sequences of 53 organisms showed a positive correlation between the size of a genome and the percentage of TEs it contains, as well as a negative correlation between size and the CpG observed/expected (O/E) ratio in both TEs and the host DNA. TEs are seldom found at promoters and transcription start sites, but they are found more at enhancers, particularly after they have accumulated C-to-T and other mutations. Therefore, the methylation of TE DNA allows for genome expansion and also leads to new opportunities for gene control by TE-based regulatory sites.
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Hypercholesterolemia is a major risk factor for cardiovascular disease. Cholesterol homeostasis in the body is governed by the interplay between absorption, synthesis, and excretion or conversion of ...cholesterol into bile acids. A reciprocal relationship between cholesterol synthesis and absorption is known to regulate circulating cholesterol in response to dietary or therapeutic interventions. However, the degree to which these factors affect synthesis and absorption and the extent to which one vector shifts in response to the other are not thoroughly understood. Also, huge inter-individual variability exists in the manner in which the two systems act in response to any cholesterol-lowering treatment. Various factors are known to account for this variability and in light of recent experimental advances new players such as gene–gene interactions, gene–environmental effects, and gut microbiome hold immense potential in offering an explanation to the complex traits of inter-individual variability in human cholesterol metabolism. In this context, the objective of the present review is to provide an overview on cholesterol metabolism and discuss the role of potential factors such as genetics, epigenetics, epistasis, and gut microbiome, as well as other regulators in modulating cholesterol metabolism, especially emphasizing the reciprocal relationship between cholesterol synthesis and absorption. Furthermore, an evaluation of the implications of this push–pull mechanism on cholesterol-lowering strategies is presented.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
DNA-demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analyses in colorectal cancer cells, we ...demonstrate that low-dose 5-AZA-CdR targets colorectal cancer-initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS RNA recognition pathway, and downstream activation of IRF7. Indeed, disruption of virus recognition pathways, by individually knocking down MDA5, MAVS, or IRF7, inhibits the ability of 5-AZA-CdR to target colorectal CICs and significantly decreases 5-AZA-CdR long-term growth effects. Moreover, transfection of dsRNA into CICs can mimic the effects of 5-AZA-CdR. Together, our results represent a major shift in understanding the anti-tumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs.
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•5-AZA-CdR induces formation of dsRNAs and activation of the MDA5/MAVS/IRF7 pathway•An anti-proliferative response to DNA demethylation is mediated by viral mimicry•5-AZA-CdR-mediated targeting of CICs is mainly mediated by viral mimicry•The MDA5/MAVS/IRF7 pathway is a potentially druggable target against colorectal cancer
Anti-tumor DNA-demethylating agents act by inducing transcription of endogenous dsRNAs that activate the viral recognition and interferon response pathway. This anti-viral response reduces proliferation of colorectal cancer-initiating cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epigenetic Determinants of Cancer Baylin, Stephen B; Jones, Peter A
Cold Spring Harbor perspectives in biology,
2016-Sep-01, 2016-09-00, 20160901, Volume:
8, Issue:
9
Journal Article
Peer reviewed
Open access
SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone ...modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. Epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. The application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.
DNA methylation patterns are set up early in mammalian development and are then copied during the division of somatic cells. A long-established model for the maintenance of these patterns explains ...some, but not all, of the data that are now available. We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA.
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Targeting the cancer epigenome for therapy Jones, Peter A; Issa, Jean-Pierre J; Baylin, Stephen
Nature reviews. Genetics,
10/2016, Volume:
17, Issue:
10
Journal Article
Peer reviewed
Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic ...and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.
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