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DNA sequence context as a marker of CpG methylation instability in normal and cancer tissues.

ABSTRACT: DNA methylation alterations are related to multiple molecular mechanisms. The DNA context of CpG sites plays a crucial role in the maintenance and stability of methylation patterns. The quantitative relationship between DNA composition and DNA methylation has been studied in normal as well as pathological conditions, showing that DNA methylation status is highly dependent on the local sequence context. In this work, we describe this relationship by analyzing the DNA sequence context associated to methylation profiles in both physiological and pathological conditions. In particular, we used DNA motifs to describe methylation stability patterns in normal tissues and aberrant methylation events in cancer lesions. In this manuscript, we show how different groups of DNA sequences can be related to specific epigenetic events, across normal and cancer tissues, and provide a thorough structural and functional characterization of these sequences.

SUBMITTER: Scala G

PROVIDER: S-EPMC6997448 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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DNA sequence context as a marker of CpG methylation instability in normal and cancer tissues.

Scala Giovanni G Federico Antonio A Palumbo Domenico D Cocozza Sergio S Greco Dario D

Scientific reports 20200203 1

DNA methylation alterations are related to multiple molecular mechanisms. The DNA context of CpG sites plays a crucial role in the maintenance and stability of methylation patterns. The quantitative relationship between DNA composition and DNA methylation has been studied in normal as well as pathological conditions, showing that DNA methylation status is highly dependent on the local sequence context. In this work, we describe this relationship by analyzing the DNA sequence context associated t ...[more]

PMID: 32015379

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Project description:Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island-dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations.

Dataset Information

DNA sequence context as a marker of CpG methylation instability in normal and cancer tissues.

Publications

DNA sequence context as a marker of CpG methylation instability in normal and cancer tissues.

Similar Datasets

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