Special Issue "Role of DNA Methyltransferases in the Epigenome"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (16 November 2018).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Albert Jeltsch
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Guest Editor
University of Stuttgart, Institute of Biochemistry and Technical Biochemistry, Department of Biochemistry, Stuttgart, Germany
Interests: DNA methyltransferases; DNA methylation; protein methyltransferases; reading domains; molecular epigenetics; synthetic biology; molecular enzymology
Special Issues and Collections in MDPI journals
Dr. Humaira Gowher
Website
Guest Editor
Purdue University, Department of Biochemistry, West Lafayette, Indiana 47907, USA
Interests: cell culture; gene expression; DNA sequencing; genomics; gene regulation; next generation sequencing; epigenetics; regulation of gene expression; transcription; transcriptional regulation; DNA methylation; gene expression and chromatin biology; chromatin; methylation; histone modification; epigenomics; ChIP-sequencing; chromatin remodeling; chromatin structure; chromatin biology; embryonic stem cell culture and differentiation; enhancer regulation

Special Issue Information

Dear Colleagues,

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 an essential role in development by orchestrating the generation and maintenance of the phenotypic diversity of human cell types. Recent years have brought spectacular advances in our understanding of the mechanism, function and regulation of DNA methyltransferases through their interaction with other epigenome modifications, chromatin factors and post-translational modifications. This Special Issue of Genes will cover all these aspects of epigenome regulation by DNA methyltransferases. Manuscripts describing the targeting and regulation of DNA methyltransferases by interacting factors, DNA binding proteins, non-coding RNAs, post-translational modifications and by conformational changes are within the scope of this issue. Additionally, biochemical and genetic studies addressing the effects of DNA methyltransferases on cellular differentiation and the development of diseases, as well as studies investigating the effects of DNA methyltransferases on other marks of the epigenome network are highly welcome.

Prof. Dr. Albert Jeltsch and Prof. Dr. Humaira Gowher

Guest Editors

Manuscript Submission Information

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Keywords

  • DNA methyltransferase function
  • DNA methyltransferase mechanism
  • DNA methyltransferase regulation
  • DNA methyltransferase structure
  • DNMT1
  • DNMT3A
  • DNMT3B
  • DNA Methylation

Published Papers (10 papers)

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Editorial

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Open AccessEditorial
Editorial—Role of DNA Methyltransferases in the Epigenome
Genes 2019, 10(8), 574; https://doi.org/10.3390/genes10080574 - 30 Jul 2019
Cited by 2
Abstract
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

Review

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Open AccessReview
Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases
Genes 2019, 10(5), 369; https://doi.org/10.3390/genes10050369 - 14 May 2019
Cited by 11
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
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Open AccessReview
DNA Methylation Reprogramming during Mammalian Development
Genes 2019, 10(4), 257; https://doi.org/10.3390/genes10040257 - 29 Mar 2019
Cited by 41
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
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Open AccessReview
The Roles of Human DNA Methyltransferases and Their Isoforms in Shaping the Epigenome
Genes 2019, 10(2), 172; https://doi.org/10.3390/genes10020172 - 23 Feb 2019
Cited by 30
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
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Open AccessReview
Coordinated Dialogue between UHRF1 and DNMT1 to Ensure Faithful Inheritance of Methylated DNA Patterns
Genes 2019, 10(1), 65; https://doi.org/10.3390/genes10010065 - 18 Jan 2019
Cited by 13
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
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Open AccessReview
Structural Basis of DNMT1 and DNMT3A-Mediated DNA Methylation
Genes 2018, 9(12), 620; https://doi.org/10.3390/genes9120620 - 11 Dec 2018
Cited by 14
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
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Open AccessReview
Mechanisms of DNA Methyltransferase Recruitment in Mammals
Genes 2018, 9(12), 617; https://doi.org/10.3390/genes9120617 - 10 Dec 2018
Cited by 12
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
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Open AccessReview
The Growing Complexity of UHRF1-Mediated Maintenance DNA Methylation
Genes 2018, 9(12), 600; https://doi.org/10.3390/genes9120600 - 03 Dec 2018
Cited by 13
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
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Open AccessReview
Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes
Genes 2018, 9(11), 566; https://doi.org/10.3390/genes9110566 - 21 Nov 2018
Cited by 25
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
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Other

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Open AccessErratum
Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes
Genes 2019, 10(5), 388; https://doi.org/10.3390/genes10050388 - 21 May 2019
Cited by 1
Abstract
The authors wish to make the following correction to their paper [...] Full article
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