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      Beyond Restriction Modification: Epigenomic Roles of DNA Methylation in Prokaryotes

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      Annual Review of Microbiology
      Annual Reviews

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          Abstract

          The amount of bacterial and archaeal genome sequence and methylome data has greatly increased over the last decade, enabling new insights into the functional roles of DNA methylation in these organisms. Methyltransferases (MTases), the enzymes responsible for DNA methylation, are exchanged between prokaryotes through horizontal gene transfer and can function either as part of restriction-modification systems or in apparent isolation as single (orphan) genes. The patterns of DNA methylation they confer on the host chromosome can have significant effects on gene expression, DNA replication, and other cellular processes. Some processes require very stable patterns of methylation, resulting in conservation of persistent MTases in a particular lineage. Other processes require patterns that are more dynamic yet more predictable than what is afforded by horizontal gene transfer and gene loss, resulting in phase-variable or recombination-driven MTase alleles. In this review, we discuss what is currently known about the functions of DNA methylation in prokaryotes in light of these evolutionary patterns.

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          Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.

          DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
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            Hypomethylation distinguishes genes of some human cancers from their normal counterparts.

            It has been suggested that cancer represents an alteration in DNA, heritable by progeny cells, that leads to abnormally regulated expression of normal cellular genes; DNA alterations such as mutations, rearrangements and changes in methylation have been proposed to have such a role. Because of increasing evidence that DNA methylation is important in gene expression (for review see refs 7, 9-11), several investigators have studied DNA methylation in animal tumours, transformed cells and leukaemia cells in culture. The results of these studies have varied; depending on the techniques and systems used, an increase, decrease, or no change in the degree of methylation has been reported. To our knowledge, however, primary human tumour tissues have not been used in such studies. We have now examined DNA methylation in human cancer with three considerations in mind: (1) the methylation pattern of specific genes, rather than total levels of methylation, was determined; (2) human cancers and adjacent analogous normal tissues, unconditioned by culture media, were analysed; and (3) the cancers were taken from patients who had received neither radiation nor chemotherapy. In four of five patients studied, representing two histological types of cancer, substantial hypomethylation was found in genes of cancer cells compared with their normal counterparts. This hypomethylation was progressive in a metastasis from one of the patients.
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              Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

              5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.
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                Author and article information

                Journal
                Annual Review of Microbiology
                Annu. Rev. Microbiol.
                Annual Reviews
                0066-4227
                1545-3251
                October 08 2021
                October 08 2021
                : 75
                : 1
                : 129-149
                Affiliations
                [1 ]New England Biolabs, Ipswich, Massachusetts 01938, USA;,
                Article
                10.1146/annurev-micro-040521-035040
                34314594
                15909a09-20d0-4142-a05f-91e51f318312
                © 2021
                History

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