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Experimental & Molecular Medicine Apr 2017Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and... (Review)
Review
Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and globular domains of histones and their levels are precisely balanced by the action of methyltransferases ('writers') and demethylases ('erasers'). In addition, distinct effector proteins ('readers') recognize specific methyl-lysines in a manner that depends on the neighboring amino-acid sequence and methylation state. Misregulation of histone lysine methylation has been implicated in several cancers and developmental defects. Therefore, histone lysine methylation has been considered a potential therapeutic target, and clinical trials of several inhibitors of this process have shown promising results. A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments. This review summarizes enzymes responsible for histone lysine methylation and demethylation and how histone lysine methylation contributes to various biological processes.
Topics: Animals; Histone Code; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Protein Processing, Post-Translational
PubMed: 28450737
DOI: 10.1038/emm.2017.11 -
The Journal of Biological Chemistry Apr 2022Many proteins are modified by posttranslational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in... (Review)
Review
Many proteins are modified by posttranslational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in modulating protein function and thus in optimizing and regulating cellular and physiological processes. Research has mainly focused on nuclear and cytosolic protein methylation, but it has been known for many years that also mitochondrial proteins are methylated. During the last decade, significant progress has been made on identifying the MTases responsible for mitochondrial protein methylation and addressing its functional significance. In particular, several novel human MTases have been uncovered that methylate lysine, arginine, histidine, and glutamine residues in various mitochondrial substrates. Several of these substrates are key components of the bioenergetics machinery, e.g., respiratory Complex I, citrate synthase, and the ATP synthase. In the present review, we report the status of the field of mitochondrial protein methylation, with a particular emphasis on recently discovered human MTases. We also discuss evolutionary aspects and functional significance of mitochondrial protein methylation and present an outlook for this emergent research field.
Topics: Humans; Methylation; Methyltransferases; Mitochondria; Mitochondrial Proteins; Protein Processing, Post-Translational
PubMed: 35247388
DOI: 10.1016/j.jbc.2022.101791 -
International Journal of Biological... 2023Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes... (Review)
Review
Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.
Topics: Humans; Arginine; Methylation; Histones; Gene Expression Regulation; Virus Diseases
PubMed: 37928266
DOI: 10.7150/ijbs.89498 -
American Journal of Physiology. Cell... Oct 2019Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. -methyladenosine (mA) methylation is the most abundant epigenetic...
Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. -methyladenosine (mA) methylation is the most abundant epigenetic modification of mammalian mRNA, but its role in macrophage polarization is still completely unknown. Here, we show that the mA-catalytic enzyme methyltransferase like 3 (METTL3) is specifically upregulated following the M1 polarization of mouse macrophages. Furthermore, METTL3 knockdown through siRNA transfection markedly inhibited M1, but enhanced M2, macrophage polarization. Conversely, its overexpression via plasmid transfection greatly facilitated M1, but attenuated M2, macrophage polarization. Further methylated RNA immunoprecipitation and in vitro mA methylation assays suggested that METTL3 directly methylates mRNA encoding signal transducer and activator of transcription 1 (STAT1), a master transcription factor controlling M1 macrophage polarization, at its coding sequence and 3'-untranslated regions. In addition, METTL3-mediated mRNA methylation significantly increased mRNA stability and subsequently upregulated STAT1 expression. In conclusion, METTL3 drives M1 macrophage polarization by directly methylating mRNA, potentially serving as an anti-inflammatory target.
Topics: Adenosine; Animals; Anti-Inflammatory Agents; Gene Expression Regulation; Macrophage Activation; Macrophages; Male; Methylation; Methyltransferases; Mice, Inbred C57BL; RNA, Messenger; STAT1 Transcription Factor
PubMed: 31365297
DOI: 10.1152/ajpcell.00212.2019 -
Seminars in Cancer Biology Aug 2022Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the... (Review)
Review
Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.
Topics: Histones; Humans; Lysine; Methylation; Methyltransferases; Neoplasms
PubMed: 33753223
DOI: 10.1016/j.semcancer.2021.03.015 -
Molecules (Basel, Switzerland) Oct 2018DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and... (Review)
Review
DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of disease conditions. Nevertheless, the full mechanisms by which DNA methylation information is interpreted and translated into genomic responses is not yet fully understood. Methyl-CpG binding proteins (MBPs) function as important mediators of this essential process by selectively reading DNA methylation signals and translating this information into down-stream cellular outcomes. The Cys₂His₂ zinc finger scaffold is one of the most abundant DNA binding motifs found within human transcription factors, yet only a few zinc finger containing proteins capable of conferring selectivity for mCpG over CpG sites have been characterized. This review summarizes our current structural understanding for the mechanisms by which the zinc finger MBPs evaluated to date read this essential epigenetic mark. Further, some of the biological implications for mCpG readout elicited by this family of MBPs are discussed.
Topics: CpG Islands; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Humans; Signal Transduction; Transcription Factors; Zinc Fingers
PubMed: 30301273
DOI: 10.3390/molecules23102555 -
Trends in Biochemical Sciences May 2013Methylated lysine and arginine residues in histones represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction... (Review)
Review
Methylated lysine and arginine residues in histones represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction domains modulates transcription. Although some methylating enzymes appear to be histone specific, many can modify histone and non-histone substrates and an increasing number are specific for non-histone substrates. Some of the non-histone substrates can also be involved in transcription, but a distinct subset of protein methylation reactions occurs at residues buried deeply in ribosomal proteins that may function in protein-RNA interactions rather than protein-protein interactions. Additionally, recent work has identified enzymes that catalyze protein methylation reactions at new sites in ribosomal and other proteins. These reactions include modifications of histidine and cysteine residues as well as the N terminus.
Topics: Animals; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Protein Interaction Domains and Motifs; Proteins; Ribosomal Proteins; Transcription Factors
PubMed: 23490039
DOI: 10.1016/j.tibs.2013.02.004 -
Journal of the History of Biology Dec 2022DNA methylation is a quintessential epigenetic mechanism. Widely considered a stable regulator of gene silencing, it represents a form of "molecular braille," chemically... (Review)
Review
DNA methylation is a quintessential epigenetic mechanism. Widely considered a stable regulator of gene silencing, it represents a form of "molecular braille," chemically printed on DNA to regulate its structure and the expression of genetic information. However, there was a time when methyl groups simply existed in cells, mysteriously speckled across the cytosine building blocks of DNA. Why was the code of life chemically modified, apparently by "no accident of enzyme action" (Wyatt 1951)? If all cells in a body share the same genome sequence, how do they adopt unique functions and maintain stable developmental states? Do cells remember? In this historical perspective, I review epigenetic history and principles and the tools, key scientists, and concepts that brought us the synthesis and discovery of prokaryotic and eukaryotic methylated DNA. Drawing heavily on Gerard Wyatt's observation of asymmetric levels of methylated DNA across species, as well as to a pair of visionary 1975 DNA methylation papers, 5-methylcytosine is connected to DNA methylating enzymes in bacteria, the maintenance of stable cellular states over development, and to the regulation of gene expression through protein-DNA binding. These works have not only shaped our views on heritability and gene regulation but also remind us that core epigenetic concepts emerged from the intrinsic requirement for epigenetic mechanisms to exist. Driven by observations across prokaryotic and eukaryotic worlds, epigenetic systems function to access and interpret genetic information across all forms of life. Collectively, these works offer many guiding principles for our epigenetic understanding for today, and for the next generation of epigenetic inquiry in a postgenomics world.
Topics: DNA Methylation; Epigenesis, Genetic; DNA; Gene Silencing; Eukaryota; Writing
PubMed: 36239862
DOI: 10.1007/s10739-022-09691-8 -
Epigenomics Oct 2010The combinatorial pattern of DNA and histone modifications constitutes an epigenetic 'code' that shapes gene-expression patterns by enabling or restricting the... (Review)
Review
The combinatorial pattern of DNA and histone modifications constitutes an epigenetic 'code' that shapes gene-expression patterns by enabling or restricting the transcriptional potential of genomic domains. DNA methylation is associated with histone modifications, particularly the absence of histone H3 lysine 4 methylation (H3K4me0) and the presence of H3K9 methylation. This article focuses on three protein domains (ATRX-Dnmt3-Dnmt3L [ADD], Cys-X-X-Cys [CXXC] and the methyl-CpG-binding domain [MBD]) and the functional implications of domain architecture in the mechanisms linking histone methylation and DNA methylation in mammalian cells. The DNA methyltransferase DNMT3a and its accessory protein Dnmt 3L contain a H3K4me0-interacting ADD domain that links the DNA methylation reaction with unmodified H3K4. The H3K4 methyltransferase MLL1 contains a CpG-interacting CXXC domain that may couple the H3K4 methylation reaction to unmethylated DNA. Another H3K4 methyltransferase, SET1, although lacking an intrinsic CXXC domain, interacts directly with an accessory protein CFP1 that contains the same domain. The H3K9 methyltransferase SETDB1 contains a putative MBD that potentially links the H3K4 methylation reaction to methylated DNA or may do so through the interaction with the MBD containing protein MBD1. Finally, we consider the domain structure of the DNA methyltransferase DNMT1, its accessory protein UHRF1 and their associated proteins, and propose a mechanism by which DNA methylation and histone methylation may be coordinately maintained through mitotic cell division, allowing for the transmission of parental DNA and for the histone methylation patterns to be copied to newly replicated chromatin.
Topics: CpG Islands; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Replication; Gene Expression Regulation; Histones; Humans; Methylation; Models, Biological; Protein Structure, Tertiary
PubMed: 21339843
DOI: 10.2217/epi.10.44 -
Nature Reviews. Genetics Aug 2016Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or... (Review)
Review
Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.
Topics: DNA; DNA Methylation; DNA-Binding Proteins; Humans; Transcription Factors; Transcription, Genetic
PubMed: 27479905
DOI: 10.1038/nrg.2016.83