Editorial

4 pages, 191 KiB

Open AccessEditorial

Editorial—Role of DNA Methyltransferases in the Epigenome

by Albert Jeltsch and Humaira Gowher

Genes 2019, 10(8), 574; https://doi.org/10.3390/genes10080574 - 30 Jul 2019

Cited by 9 | Viewed by 3166

DNA methylation, a modification found in most species, regulates chromatin functions in conjunction with other epigenome modifications, such as histone post-translational modifications and non-coding RNAs. In mammals, DNA methylation has essential roles in development by orchestrating the generation and maintenance of the phenotypic [...] Read more.

DNA methylation, a modification found in most species, regulates chromatin functions in conjunction with other epigenome modifications, such as histone post-translational modifications and non-coding RNAs. In mammals, DNA methylation has essential roles in development by orchestrating the generation and maintenance of the phenotypic diversity of human cell types. This Special Issue of Genes contains eight review articles, which cover several aspects of epigenome regulation by DNA methyltransferases (DNMTs), the enzymes responsible for the introduction of DNA methylation. The manuscripts present the most recent advances regarding the structure and function of DNMTs, their targeting and regulation by interacting factors and chromatin modifications, and the roles of DNMTs in mammalian development and human diseases. However, many aspects of these important enzymes are still insufficiently understood. Potential directions of future work are the regulation of DNMTs by post-translational modifications and their connection to cellular signaling and second messenger cascades on one hand and to large multifactorial epigenetic chromatin circuits on the other. Additionally, technical advancements, including the availability of designer nucleosomes and the rapid development of cryo-electron microscopy are expected to trigger breakthrough discoveries in this exciting field. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

Review

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16 pages, 3625 KiB

Open AccessReview

Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases

by Allison B. Norvil, Debapriya Saha, Mohd Saleem Dar and Humaira Gowher

Genes 2019, 10(5), 369; https://doi.org/10.3390/genes10050369 - 14 May 2019

Cited by 19 | Viewed by 5445

Abstract

Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have [...] Read more.

Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have helped identify mutations and genetic alterations of DNMTs in various diseases that have a potential to affect the biological function and activity of these enzymes. Several of these mutations are germline-transmitted and associated with a number of hereditary disorders, which are potentially caused by aberrant DNA methylation patterns in the regulatory compartments of the genome. These hereditary disorders usually cause neurological dysfunction, growth defects, and inherited cancers. Biochemical and biological characterization of DNMT variants can reveal the molecular mechanism of these enzymes and give insights on their specific functions. In this review, we introduce roles and regulation of DNA methylation and DNMTs. We discuss DNMT mutations that are associated with rare diseases, the characterized effects of these mutations on enzyme activity and provide insights on their potential effects based on the known crystal structure of these proteins. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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18 pages, 1126 KiB

Open AccessReview

DNA Methylation Reprogramming during Mammalian Development

by Yang Zeng and Taiping Chen

Genes 2019, 10(4), 257; https://doi.org/10.3390/genes10040257 - 29 Mar 2019

Cited by 198 | Viewed by 16149

Abstract

DNA methylation (5-methylcytosine, 5mC) is a major form of DNA modification in the mammalian genome that plays critical roles in chromatin structure and gene expression. In general, DNA methylation is stably maintained in somatic tissues. However, DNA methylation patterns and levels show dynamic [...] Read more.

DNA methylation (5-methylcytosine, 5mC) is a major form of DNA modification in the mammalian genome that plays critical roles in chromatin structure and gene expression. In general, DNA methylation is stably maintained in somatic tissues. However, DNA methylation patterns and levels show dynamic changes during development. Specifically, the genome undergoes two waves of global demethylation and remethylation for the purpose of producing the next generation. The first wave occurs in the germline, initiated with the erasure of global methylation in primordial germ cells (PGCs) and completed with the establishment of sex-specific methylation patterns during later stages of germ cell development. The second wave occurs after fertilization, including the erasure of most methylation marks inherited from the gametes and the subsequent establishment of the embryonic methylation pattern. The two waves of DNA methylation reprogramming involve both distinct and shared mechanisms. In this review article, we provide an overview of the key reprogramming events, focusing on the important players in these processes, including DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family of 5mC dioxygenases. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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18 pages, 1279 KiB

Open AccessReview

The Roles of Human DNA Methyltransferases and Their Isoforms in Shaping the Epigenome

by Hemant Gujar, Daniel J. Weisenberger and Gangning Liang

Genes 2019, 10(2), 172; https://doi.org/10.3390/genes10020172 - 23 Feb 2019

Cited by 121 | Viewed by 16124

Abstract

A DNA sequence is the hard copy of the human genome and it is a driving force in determining the physiological processes in an organism. Concurrently, the chemical modification of the genome and its related histone proteins is dynamically involved in regulating physiological [...] Read more.

A DNA sequence is the hard copy of the human genome and it is a driving force in determining the physiological processes in an organism. Concurrently, the chemical modification of the genome and its related histone proteins is dynamically involved in regulating physiological processes and diseases, which overall constitutes the epigenome network. Among the various forms of epigenetic modifications, DNA methylation at the C-5 position of cytosine in the cytosine–guanine (CpG) dinucleotide is one of the most well studied epigenetic modifications. DNA methyltransferases (DNMTs) are a family of enzymes involved in generating and maintaining CpG methylation across the genome. In mammalian systems, DNA methylation is performed by DNMT1 and DNMT3s (DNMT3A and 3B). DNMT1 is predominantly involved in the maintenance of DNA methylation during cell division, while DNMT3s are involved in establishing de novo cytosine methylation and maintenance in both embryonic and somatic cells. In general, all DNMTs require accessory proteins, such as ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domain 1 (UHRF1) or DNMT3-like (DNMT3L), for their biological function. This review mainly focuses on the role of DNMT3B and its isoforms in de novo methylation and maintenance of DNA methylation, especially with respect to their role as an accessory protein. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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14 pages, 957 KiB

Open AccessReview

Coordinated Dialogue between UHRF1 and DNMT1 to Ensure Faithful Inheritance of Methylated DNA Patterns

by Christian Bronner, Mahmoud Alhosin, Ali Hamiche and Marc Mousli

Genes 2019, 10(1), 65; https://doi.org/10.3390/genes10010065 - 18 Jan 2019

Cited by 67 | Viewed by 8881

Abstract

DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is an epigenetic mark that needs to be faithfully replicated during mitosis in order to maintain cell phenotype during successive cell divisions. This epigenetic mark is located on the 5′-carbon of the cytosine mainly within cytosine–phosphate–guanine [...] Read more.

DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is an epigenetic mark that needs to be faithfully replicated during mitosis in order to maintain cell phenotype during successive cell divisions. This epigenetic mark is located on the 5′-carbon of the cytosine mainly within cytosine–phosphate–guanine (CpG) dinucleotides. DNA methylation is asymmetrically positioned on both DNA strands, temporarily generating a hemi-methylated state after DNA replication. Hemi-methylation is a particular status of DNA that is recognized by ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) through its SET- (Su(var)3-9, Enhancer-of-zeste and Trithorax) and RING-associated (SRA) domain. This interaction is considered to be involved in the recruitment of DNMT1 to chromatin in order to methylate the adequate cytosine on the newly synthetized DNA strand. The UHRF1/DNMT1 tandem plays a pivotal role in the inheritance of DNA methylation patterns, but the fine-tuning mechanism remains a mystery. Indeed, because DNMT1 experiences difficulties in finding the cytosine to be methylated, it requires the help of a guide, i.e., of UHRF1, which exhibits higher affinity for hemi-methylated DNA vs. non-methylated DNA. Two models of the UHRF1/DNMT1 dialogue were suggested to explain how DNMT1 is recruited to chromatin: (i) an indirect communication via histone H3 ubiquitination, and (ii) a direct interaction of UHRF1 with DNMT1. In the present review, these two models are discussed, and we try to show that they are compatible with each other. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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20 pages, 10847 KiB

Open AccessReview

Structural Basis of DNMT1 and DNMT3A-Mediated DNA Methylation

by Wendan Ren, Linfeng Gao and Jikui Song

Genes 2018, 9(12), 620; https://doi.org/10.3390/genes9120620 - 11 Dec 2018

Cited by 75 | Viewed by 13851

Abstract

DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which [...] Read more.

DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which are responsible for installing DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which is essential for propagating DNA methylation patterns during replication. Both groups of DNMTs are multi-domain proteins, containing a large N-terminal regulatory region in addition to the C-terminal methyltransferase domain. Recent structure-function investigations of the individual domains or large fragments of DNMT1 and DNMT3A have revealed the molecular basis for their substrate recognition and specificity, intramolecular domain-domain interactions, as well as their crosstalk with other epigenetic mechanisms. These studies highlight a multifaceted regulation for both DNMT1 and DNMT3A/3B, which is essential for the precise establishment and maintenance of lineage-specific DNA methylation patterns in cells. This review summarizes current understanding of the structure and mechanism of DNMT1 and DNMT3A-mediated DNA methylation, with emphasis on the functional cooperation between the methyltransferase and regulatory domains. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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18 pages, 1557 KiB

Open AccessReview

Mechanisms of DNA Methyltransferase Recruitment in Mammals

by Marthe Laisné, Nikhil Gupta, Olivier Kirsh, Sriharsa Pradhan and Pierre-Antoine Defossez

Genes 2018, 9(12), 617; https://doi.org/10.3390/genes9120617 - 10 Dec 2018

Cited by 31 | Viewed by 7830

Abstract

DNA methylation is an essential epigenetic mark in mammals. The proper distribution of this mark depends on accurate deposition and maintenance mechanisms, and underpins its functional role. This, in turn, depends on the precise recruitment and activation of de novo and maintenance DNA [...] Read more.

DNA methylation is an essential epigenetic mark in mammals. The proper distribution of this mark depends on accurate deposition and maintenance mechanisms, and underpins its functional role. This, in turn, depends on the precise recruitment and activation of de novo and maintenance DNA methyltransferases (DNMTs). In this review, we discuss mechanisms of recruitment of DNMTs by transcription factors and chromatin modifiers—and by RNA—and place these mechanisms in the context of biologically meaningful epigenetic events. We present hypotheses and speculations for future research, and underline the fundamental and practical benefits of better understanding the mechanisms that govern the recruitment of DNMTs. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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12 pages, 2336 KiB

Open AccessReview

The Growing Complexity of UHRF1-Mediated Maintenance DNA Methylation

by Si Xie and Chengmin Qian

Genes 2018, 9(12), 600; https://doi.org/10.3390/genes9120600 - 03 Dec 2018

Cited by 32 | Viewed by 6645

Abstract

Mammalian DNMT1 is mainly responsible for maintenance DNA methylation that is critical in maintaining stem cell pluripotency and controlling lineage specification during early embryonic development. A number of studies have demonstrated that DNMT1 is an auto-inhibited enzyme and its enzymatic activity is allosterically [...] Read more.

Mammalian DNMT1 is mainly responsible for maintenance DNA methylation that is critical in maintaining stem cell pluripotency and controlling lineage specification during early embryonic development. A number of studies have demonstrated that DNMT1 is an auto-inhibited enzyme and its enzymatic activity is allosterically regulated by a number of interacting partners. UHRF1 has previously been reported to regulate DNMT1 in multiple ways, including control of substrate specificity and the proper genome targeting. In this review, we discuss the recent advances in our understanding of the regulation of DNMT1 enzymatic activity by UHRF1 and highlight a number of unresolved questions. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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20 pages, 5230 KiB

Open AccessReview

Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes

by Albert Jeltsch, Julian Broche and Pavel Bashtrykov

Genes 2018, 9(11), 566; https://doi.org/10.3390/genes9110566 - 21 Nov 2018

Cited by 49 | Viewed by 7332

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)

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