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Expert Reviews in Molecular Medicine Mar 2021Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological... (Review)
Review
Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological activities and human diseases. To aid in the diagnostic and therapeutic design for cancer treatment utilising methylation, this review provides a boutique yet comprehensive overview on methylation at different levels including the mechanisms, cross-talking and clinical implications with a particular focus on cancers. We conclude that DNA methylation is the sole type of methylation that has been largely translated into clinics and used for, mostly, early diagnosis. Translating the onco-therapeutic and prognostic values of RNA and protein methylations into clinical use deserves intensive efforts. Simultaneous examination of methylations at multiple levels or together with other forms of molecular markers represents an interesting research direction with profound clinical translational potential.
Topics: DNA Methylation; Humans; Neoplasms; Protein Processing, Post-Translational
PubMed: 33787478
DOI: 10.1017/erm.2021.4 -
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 -
Proceedings of the National Academy of... Apr 2023The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy...
The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.
Topics: Female; Humans; Methylation; DNA Copy Number Variations; 5-Methylcytosine; DNA; Mutation; Neoplasms; DNA Methylation
PubMed: 37014860
DOI: 10.1073/pnas.2220704120 -
RNA Biology Sep 2017Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by... (Review)
Review
Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by modified tRNA-bases or silencing and reactivation of genes by methylation and demethylation of cytosine in promoter regions. Especially dynamic methylation of adenine and cytosine is essential for cells to adapt to their environment or for the development of complex organisms from a single cell. Errors in the cytosine methylation pattern are associated with most types of cancer and bacteria use methylated nucleobases to resist antibiotics. This Point of View wants to shed light on the known and potential chemistry of DNA and RNA methylation and demethylation. Understanding the chemistry of these processes on a molecular level is the first step towards a deeper knowledge about their regulation and function and will help us to find ways how nucleobase methylation can be manipulated to treat diseases.
Topics: Animals; DNA; DNA Methylation; Demethylation; Epigenesis, Genetic; Humans; Methylation; RNA
PubMed: 28440690
DOI: 10.1080/15476286.2017.1318241 -
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 -
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 -
The ISME Journal Aug 2023Dimethylsulfide (DMS) is the major biosulfur source emitted to the atmosphere with key roles in global sulfur cycling and potentially climate regulation. The main...
Dimethylsulfide (DMS) is the major biosulfur source emitted to the atmosphere with key roles in global sulfur cycling and potentially climate regulation. The main precursor of DMS is thought to be dimethylsulfoniopropionate. However, hydrogen sulfide (HS), a widely distributed and abundant volatile in natural environments, can be methylated to DMS. The microorganisms and the enzymes that convert HS to DMS, and their importance in global sulfur cycling were unknown. Here we demonstrate that the bacterial MddA enzyme, previously known as a methanethiol S-methyltransferase, could methylate inorganic HS to DMS. We determine key residues involved in MddA catalysis and propose the mechanism for HS S-methylation. These results enabled subsequent identification of functional MddA enzymes in abundant haloarchaea and a diverse range of algae, thus expanding the significance of MddA mediated HS methylation to other domains of life. Furthermore, we provide evidence for HS S-methylation being a detoxification strategy in microorganisms. The mddA gene was abundant in diverse environments including marine sediments, lake sediments, hydrothermal vents and soils. Thus, the significance of MddA-driven methylation of inorganic HS to global DMS production and sulfur cycling has likely been considerably underestimated.
Topics: Hydrogen Sulfide; Methylation; Sulfides; Sulfur
PubMed: 37179443
DOI: 10.1038/s41396-023-01430-z