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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 factors that mediate the crosstalk between DNA methylation and chromatin modifications. Finally, we describe recent advances regarding the methylation of non-CpG sites, methylation of adenine residues in human cells and methylation of mitochondrial DNA. At several places, we highlight controversial findings or open questions demanding future experimental work.

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As part of the epigenetic network, DNA methylation is a major regulator of chromatin structure and function. In mammals, it mainly occurs at palindromic CpG sites, but asymmetric methylation at non-CpG sites is also observed. Three enzymes are involved in the generation and maintenance of DNA methylation patterns. DNMT1 has high preference for hemimethylated CpG sites, and DNMT3A and DNMT3B equally methylate unmethylated and hemimethylated DNA, and also introduce non-CpG methylation. Here, we review recent observations and novel insights into the structure and function of mammalian DNMTs (DNA methyltransferases), including new structures of DNMT1 and DNMT3A, data on their mechanism, regulation by post-translational modifications and on the function of DNMTs in cells. In addition, we present news findings regarding the allosteric regulation and targeting of DNMTs by chromatin modifications and chromatin proteins. In combination, the recent publications summarized here impressively illustrate the intensity of ongoing research in this field. They provide a deeper understanding of key mechanistic properties of DNMTs, but they also document still unsolved issues, which need to be addressed in future research.

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Epigenome editing refers to the directed alteration of chromatin marks at specific genomic loci by using targeted EpiEffectors which comprise designed DNA recognition domains (zinc finger, TAL effector, or modified CRISPR/Cas9 complex) and catalytic domains from a chromatin-modifying enzyme. Epigenome editing is a promising approach for durable gene regulation, with many applications in basic research including the investigation of the regulatory functions and logic of chromatin modifications and cellular reprogramming. From a clinical point of view, targeted regulation of disease-related genes offers novel therapeutic avenues for many diseases. We review here the progress made in this field and discuss open questions in epigenetic regulation and its stability, methods to increase the specificity of epigenome editing, and improved delivery methods for targeted EpiEffectors. Future work will reveal if the approach of epigenome editing fulfills its great promise in basic research and clinical applications.

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In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene-environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of behavioral problems in children and adults. In this paper, we review the current literature on the role of epigenetics in the development of psychopathology, with a specific focus on the potential for epigenetic modifications to link nutrition and brain development. We propose a conceptual framework whereby epigenetic modifications (e.g., DNA methylation) mediate the link between micro- and macro-nutrient deficiency early in life and brain dysfunction (e.g., structural aberration, neurotransmitter perturbation), which has been linked to development of behavior problems later on in life.

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Genomic imprinting, the parent of origin-dependent expression of genes, has been discovered as a fascinating example of the control of gene expression by epigenetic processes in the human body. It affects about 100 genes, which are often involved in growth and development. In this Review, we discuss the mechanisms leading to the generation of gender-specific imprints in form of DNA methylation marks, their preservation during growth and development of the organism, and the processes that translate parental methylation marks into monoallelic gene expression. We discuss the gender-specific dimorphic nature of imprints from an evolutionary point of view and present the prevalent model that molecular imprinting mediates a conflict of interest between the parents that occurs in viviparous animals. Finally, we summarize the relevance of parental imprinting for human health.

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