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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 -
Mutation Research. Reviews in Mutation... 2019Preserving genome function and stability are paramount for ensuring cellular homeostasis, an imbalance in which can promote diseases including cancer. In the presence of... (Review)
Review
Preserving genome function and stability are paramount for ensuring cellular homeostasis, an imbalance in which can promote diseases including cancer. In the presence of DNA lesions, cells activate pathways referred to as the DNA damage response (DDR). As nuclear DNA is bound by histone proteins and organized into chromatin in eukaryotes, DDR pathways have evolved to sense, signal and repair DNA damage within the chromatin environment. Histone proteins, which constitute the building blocks of chromatin, are highly modified by post-translational modifications (PTMs) that regulate chromatin structure and function. An essential histone PTM involved in the DDR is histone methylation, which is regulated by histone methyltransferase (HMT) and histone demethylase (HDM) enzymes that add and remove methyl groups on lysine and arginine residues within proteins respectively. Methylated histones can alter how proteins interact with chromatin, including their ability to be bound by reader proteins that recognize these PTMs. Here, we review histone methylation in the context of the DDR, focusing on DNA double-strand breaks (DSBs), a particularly toxic lesion that can trigger genome instability and cell death. We provide a comprehensive overview of histone methylation changes that occur in response to DNA damage and how the enzymes and reader proteins of these marks orchestrate the DDR. Finally, as many epigenetic pathways including histone methylation are altered in cancer, we discuss the potential involvement of these pathways in the etiology and treatment of this disease.
Topics: Animals; Chromatin; DNA Damage; Histones; Humans; Methylation; Signal Transduction
PubMed: 31395347
DOI: 10.1016/j.mrrev.2017.09.003 -
Science (New York, N.Y.) May 2017The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. However, active gene regulatory elements are generally hypomethylated relative to...
The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. However, active gene regulatory elements are generally hypomethylated relative to their flanking regions, and the binding of some transcription factors (TFs) is diminished by methylation of their target sequences. By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. Most of these are in the extended homeodomain family. Structural analysis showed that homeodomain specificity for methylcytosine depends on direct hydrophobic interactions with the methylcytosine 5-methyl group. This study provides a systematic examination of the effect of an epigenetic DNA modification on human TF binding specificity and reveals that many developmentally important proteins display preference for mCpG-containing sequences.
Topics: CpG Islands; Cytosine; DNA; DNA Methylation; Dinucleoside Phosphates; Epigenesis, Genetic; Genome, Human; Humans; Protein Binding; Protein Domains; SELEX Aptamer Technique; Transcription Factors
PubMed: 28473536
DOI: 10.1126/science.aaj2239 -
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 -
Journal of Hematology & Oncology Aug 2023RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA... (Review)
Review
RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.
Topics: Humans; Methyltransferases; Adenosine; Methylation; MicroRNAs; Biology; Neoplasms
PubMed: 37533128
DOI: 10.1186/s13045-023-01477-7 -
Oncogene Jun 2023Pancreatic cancer (PC) is the most hypoxic cancer type among solid tumors. The dynamic changes of RNA N6-methyl-adenosine (m6A) contribute to tumor cells adaption to...
Pancreatic cancer (PC) is the most hypoxic cancer type among solid tumors. The dynamic changes of RNA N6-methyl-adenosine (m6A) contribute to tumor cells adaption to hypoxic microenvironmental. However, the regulatory mechanisms of hypoxia response in PC remains elusive. Here, we reported that the m6A demethylase ALKBH5 mediated a decrease of total mRNA m6A modification during hypoxia. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq) revealed transcriptome-wide gene expression alteration and identified histone deacetylase type 4 (HDAC4) as a key target gene of m6A modification under hypoxic conditionds. Mechanistically, m6A methylation recognized by m6A reader-YTHDF2 enhanced the stability of HDAC4, and then promoted glycolytic metabolism and migration of PC cells. Our assays also demonstrated that hypoxia-induced HDAC4 enhanced HIF1a protein stability, and overexpressed HIF1a promoted transcription of ALKBH5 in hypoxic pancreatic cancer cells. Together, these results found a ALKBH5/HDAC4/HIF1α positive feedback loop for cellular response to hypoxia in pancreatic cancer. Our studies uncover the crosstalk between histone acetylation and RNA methylation modification on layer of epigenetic regulation.
Topics: Humans; Methylation; Epigenesis, Genetic; Feedback; RNA; Hypoxia; Pancreatic Neoplasms; Histone Deacetylases; Repressor Proteins; AlkB Homolog 5, RNA Demethylase
PubMed: 37149664
DOI: 10.1038/s41388-023-02704-8 -
Epigenetics & Chromatin May 2022The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription,... (Review)
Review
The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription, recombination, and DNA damage response. Loss- and gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders and various cancers. Structural analyses suggest that nucleosomal components such as the linker DNA and a hydrophobic patch constituted by histone H2A and H3 are likely determinants of H3K36 methylation in addition to the histone H3 tail, which encompasses H3K36 and the catalytic SET domain. Interaction of H3K36 methyltransferases with the nucleosome collaborates with regulation of their auto-inhibitory changes fine-tunes the precision of H3K36me in mediating dimethylation by NSD2 and NSD3 as well as trimethylation by Set2/SETD2. The identification of specific structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-(H3K36me2) and tri-(H3K36me3) methylated forms of H3K36, have highlighted the intricacy of H3K36me functional significance. Here, we consolidate these findings and offer structural insight to the regulation of H3K36me2 to H3K36me3 conversion. We also discuss the mechanisms that underlie the cooperation between H3K36me and other chromatin modifications (in particular, H3K27me3, H3 acetylation, DNA methylation and N-methyladenosine in RNAs) in the physiological regulation of the epigenomic functions of chromatin.
Topics: Chromatin; Histones; Humans; Methylation; Nucleosomes; Protein Processing, Post-Translational
PubMed: 35581654
DOI: 10.1186/s13072-022-00446-7 -
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 -
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