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Reversing DNA methylation: mechanisms, genomics, and biological functions.

ABSTRACT: Methylation of cytosines in the mammalian genome represents a key epigenetic modification and is dynamically regulated during development. Compelling evidence now suggests that dynamic regulation of DNA methylation is mainly achieved through a cyclic enzymatic cascade comprised of cytosine methylation, iterative oxidation of methyl group by TET dioxygenases, and restoration of unmodified cytosines by either replication-dependent dilution or DNA glycosylase-initiated base excision repair. In this review, we discuss the mechanism and function of DNA demethylation in mammalian genomes, focusing particularly on how developmental modulation of the cytosine-modifying pathway is coupled to active reversal of DNA methylation in diverse biological processes.

SUBMITTER: Wu H

PROVIDER: S-EPMC3938284 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Reversing DNA methylation: mechanisms, genomics, and biological functions.

Wu Hao H Zhang Yi Y

Cell 20140101 1-2

Methylation of cytosines in the mammalian genome represents a key epigenetic modification and is dynamically regulated during development. Compelling evidence now suggests that dynamic regulation of DNA methylation is mainly achieved through a cyclic enzymatic cascade comprised of cytosine methylation, iterative oxidation of methyl group by TET dioxygenases, and restoration of unmodified cytosines by either replication-dependent dilution or DNA glycosylase-initiated base excision repair. In this ...[more]

PMID: 24439369

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Project description:Integrated profiling of somatic molecular alterations present in tumors is necessary to further our understanding of the tumorigenic process. We investigated the potential relationships between gene copy number alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n=23). Gene copy number (CN) alterations profiled with 500K SNP arrays and DNA methylation measured at over 750 cancer-related genes with methylation bead-arrays were examined concomitantly. Considering each probed locus, there were no instances of significantly correlated CN alteration and methylation (no loci with Q < 0.05) and averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations (Q < 0.04). In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes (P < 0.02), and there was evidence that this association was partially attributable to prevalent allele loss observed at the maintenance DNA methyltransferase DNMT1. Taken together, this work indicates a strong association between global genetic and global epigenetic dysregulation in mesothelioma rather than a discrete, local coordination of gene inactivation, and further highlights the utility and necessity of integrative genomics approaches in cancer biology. Mesotheliomas were obtained following surgical resection at Brigham and Women’s Hospital through the International Mesothelioma Program from a pilot study conducted in 2002 and an incident case series beginning in 2005 as previously described (PMIDs: 19118007 and 19638575). All patients provided informed consent under the approval of the appropriate Institutional Review Boards. Clinical information, including histologic diagnosis was obtained from pathology reports. The study pathologist confirmed the histologic diagnoses and further assessed the percent tumor from resected specimens (mean >60%). DNA extraction and methylation analysis: DNA from fresh frozen tissue and matched whole blood was isolated with QIAamp DNA mini kit (Qiagen, Valencia, CA) following the manufacturer’s protocol. Tumor DNA was modified with sodium bisulfite using the EZ DNA Methylation Kit (Zymo Research, Orange, CA). Illumina GoldenGate® methylation bead arrays interrogated 1505 CpG loci associated with 803 cancer-related genes processed at the UCSF Institute for Human Genetics, Genomics Core Facility using methods described in (28). The GoldenGate methylation data used in the analysis has been previously described (PMIDs: 19118007 and 19638575).

Dataset Information

Reversing DNA methylation: mechanisms, genomics, and biological functions.

Publications

Reversing DNA methylation: mechanisms, genomics, and biological functions.

Similar Datasets

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