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      5-methylcytosine in RNA: detection, enzymatic formation and biological functions

      1 , 2 , 3 , 4 , *

      Nucleic Acids Research

      Oxford University Press

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          Abstract

          The nucleobase modification 5-methylcytosine (m 5C) is widespread both in DNA and different cellular RNAs. The functions and enzymatic mechanisms of DNA m 5C-methylation were extensively studied during the last decades. However, the location, the mechanism of formation and the cellular function(s) of the same modified nucleobase in RNA still remain to be elucidated. The recent development of a bisulfite sequencing approach for efficient m 5C localization in various RNA molecules puts ribo-m 5C in a highly privileged position as one of the few RNA modifications whose detection is amenable to PCR-based amplification and sequencing methods. Additional progress in the field also includes the characterization of several specific RNA methyltransferase enzymes in various organisms, and the discovery of a new and unexpected link between DNA and RNA m 5C-methylation. Numerous putative RNA:m 5C-MTases have now been identified and are awaiting characterization, including the identification of their RNA substrates and their related cellular functions. In order to bring these recent exciting developments into perspective, this review provides an ordered overview of the detection methods for RNA methylation, of the biochemistry, enzymology and molecular biology of the corresponding modification enzymes, and discusses perspectives for the emerging biological functions of these enzymes.

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          Most cited references 125

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          DNA methylation landscapes: provocative insights from epigenomics.

          The genomes of many animals, plants and fungi are tagged by methylation of DNA cytosine. To understand the biological significance of this epigenetic mark it is essential to know where in the genome it is located. New techniques are making it easier to map DNA methylation patterns on a large scale and the results have already provided surprises. In particular, the conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged. Not only is promoter methylation often highly dynamic during development, but many organisms also seem to target DNA methylation specifically to the bodies of active genes.
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            Eukaryotic cytosine methyltransferases.

            Large-genome eukaryotes use heritable cytosine methylation to silence promoters, especially those associated with transposons and imprinted genes. Cytosine methylation does not reinforce or replace ancestral gene regulation pathways but instead endows methylated genomes with the ability to repress specific promoters in a manner that is buffered against changes in the internal and external environment. Recent studies have shown that the targeting of de novo methylation depends on multiple inputs; these include the interaction of repeated sequences, local states of histone lysine methylation, small RNAs and components of the RNAi pathway, and divergent and catalytically inert cytosine methyltransferase homologues that have acquired regulatory roles. There are multiple families of DNA (cytosine-5) methyltransferases in eukaryotes, and each family appears to be controlled by different regulatory inputs. Sequence-specific DNA-binding proteins, which regulate most aspects of gene expression, do not appear to be involved in the establishment or maintenance of genomic methylation patterns.
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              DNA methylation profiling of human chromosomes 6, 20 and 22

              DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                March 2010
                8 December 2009
                8 December 2009
                : 38
                : 5
                : 1415-1430
                Affiliations
                1Laboratoire ARN-RNP Maturation-Structure-Fonction, Enzymologie Moléculaire et Structurale (AREMS), UMR 7214 CNRS-UHP Faculté des Sciences et Techniques,Université Henri Poincaré, Nancy 1, Bld des Aiguillettes, BP 70239, 54506 Vandoeuvre-les-Nancy, France, 2Division of Epigenetics, German Cancer Research Center (DKFZ), 3Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany and 4Institute of Pharmacy, University of Mainz, Staudingerweg 5, 55099 Mainz, Germany
                Author notes
                *To whom correspondence should be addressed. Tel: +6131 3925731; Fax: +6131 3923779; Email: mhelm@ 123456uni-mainz.de
                Article
                gkp1117
                10.1093/nar/gkp1117
                2836557
                20007150
                © The Author(s) 2009. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Survey and Summary

                Genetics

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