Genomic patterns of DNA methylation: targets and function of an epigenetic mark (original) (raw)
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Nature Genetics, 2007
To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.
J Ocul Biol Dis Infor, 2011
Epigenetic modulation of chromatin states constitutes a vital component of the cellular repertoire of transcriptional regulatory mechanisms. The development of new technologies capable of generating genome-wide maps of chromatin modifications has re-energized the field. We are now poised to determine how species-and tissue-specific patterns of DNA methylation, in concert with other chromatin modifications, function to establish and maintain cell-and tissue-specific patterns of gene expression during normal development, cellular differentiation, and disease. This review addresses our current understanding of the major mechanisms and function of DNA methylation in vertebrates with a historical perspective and an emphasis on what is known about DNA methylation in eye development and disease.
The cell biology of DNA methylation in mammals
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008
In this review, we will provide a brief reminder of epigenetic phenomena in general, and DNA methylation in particular. We will then underline the characteristics of the in vivo organization of the genome that limit the applicability of in vitro results. We will use several examples to point out the connections between DNA methylation and nuclear architecture. Finally, we will outline some of the hopes and challenges for future research in the field. The study of DNA methylation, its effectors, and its roles, illustrates the complementarity of in vitro approaches and cell biology.
Genes
DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated...
Genomic patterns and context specific interpretation of DNA methylation
Current Opinion in Genetics & Development, 2014
Methylation of CpG dinucleotides is a reversible modification of DNA that is highly prevalent throughout mammalian genomes. Recent advances generated genomic DNA methylation maps during cellular differentiation at unprecedented resolution. Combined with functional assays this revealed that dynamics in DNA methylation coincide with changes in regulatory activity and that transcription factors play an important role in shaping methylation patterns. This tightly links DNA methylation with underlying DNA sequence features and suggests that a substantial fraction of methylation changes occur downstream of gene regulation. Here we discuss our current understanding of the context-dependent readout of DNA methylation and criteria that need to be fulfilled for this modification to be instructive for gene regulation.
Annotating the genome by DNA methylation
The International journal of developmental biology, 2017
DNA methylation plays a prominent role in setting up and stabilizing the molecular design of gene regulation and by understanding this process one gains profound insight into the underlying biology of mammals. In this article, we trace the discoveries that provided the foundations of this field, starting with the mapping of methyl groups in the genome and the experiments that helped clarify how methylation patterns are maintained through cell division. We then address the basic relationship between methyl groups and gene repression, as well as the molecular rules involved in controlling this process during development in vivo. Finally, we describe ongoing work aimed at defining the role of this modification in disease and deciphering how it may serve as a mechanism for sensing the environment.
Rethinking how DNA methylation patterns are maintained
Nature Reviews Genetics, 2009
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 is now available. We propose a new model, which suggests that maintenance of DNA methylation relies not only on the recognition of hemi-methylated DNA by the methyltransferase DNMT1 but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions containing methylated DNA. This suggestion that eukaryotes might have two classes of DNA methyltransferases (maintenance and de novo methyltransferases) implied that DNA methylation in eukaryotes
DNA methylation and epigenetic inheritance
Methods, 2002
Mammalian cell lines silence genes at low frequency by the methylation of promoter sequences. These silent genes can be reactivated at high frequency by the demethylating agent 5-azacytidine (5-aza-CR). The inactive and active epigenetic states of such genes are stably inherited. A method for silencing genes is now available. It involves treatment of permeabilized cells with 5-methyl deoxycytidine triphosphate (5-methyl dCTP) which is incorporated into DNA. The methylation of promoter sequences has been confirmed using the bisulfite genomic sequencing procedure. Methylated oligonucleotides homologous to promoter sequences might be used to specifically target and silence given genes, but results so far have not been conclusive. Treatments that silence or reactivate genes by changing DNA methylation can be referred to as epimutagens, as distinct from mutagens that act by changing DNA sequences. The epimutagen 5-aza-CR reactivates genes but has little mutagenic activity, whereas standard mutagens (such as ethyl methane sulfonate and ultraviolet light) have little reactivation activity. Nevertheless, much more information is required about the effects of DNA-damaging agents in changing DNA methylation and gene activity and also about the role of epimutations in tumor progression.