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Genes & Development Aug 2023Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of... (Review)
Review
Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of the modified (poly)peptide. In this issue of , Shimazu and colleagues (pp. 724-742) make the remarkable discovery that CARNMT1 acts as a dual-specificity histidine methyltransferase, modifying both the small-molecule dipeptide carnosine and a set of proteins, predominantly within RNA-binding C3H zinc finger (C3H ZF) motifs. As a result, CARNMT1 modulates the activity of its protein targets to affect RNA processing and metabolism, ultimately contributing an essential function during mammalian development.
Topics: Animals; Histidine; Methylation; Amino Acids; Methyltransferases; Organogenesis; Mammals
PubMed: 37673460
DOI: 10.1101/gad.351097.123 -
Chromosoma Sep 2023Chemical modifications of nucleotides expand the complexity and functional properties of genomes and transcriptomes. A handful of modifications in DNA bases are part of... (Review)
Review
Chemical modifications of nucleotides expand the complexity and functional properties of genomes and transcriptomes. A handful of modifications in DNA bases are part of the epigenome, wherein DNA methylation regulates chromatin structure, transcription, and co-transcriptional RNA processing. In contrast, more than 150 chemical modifications of RNA constitute the epitranscriptome. Ribonucleoside modifications comprise a diverse repertoire of chemical groups, including methylation, acetylation, deamination, isomerization, and oxidation. Such RNA modifications regulate all steps of RNA metabolism, including folding, processing, stability, transport, translation, and RNA's intermolecular interactions. Initially thought to influence all aspects of the post-transcriptional regulation of gene expression exclusively, recent findings uncovered a crosstalk between the epitranscriptome and the epigenome. In other words, RNA modifications feedback to the epigenome to transcriptionally regulate gene expression. The epitranscriptome achieves this feat by directly or indirectly affecting chromatin structure and nuclear organization. This review highlights how chemical modifications in chromatin-associated RNAs (caRNAs) and messenger RNAs (mRNAs) encoding factors involved in transcription, chromatin structure, histone modifications, and nuclear organization affect gene expression transcriptionally.
Topics: Epigenome; Chromatin; Gene Expression Regulation; RNA; DNA Methylation; RNA, Messenger; RNA Processing, Post-Transcriptional
PubMed: 37138119
DOI: 10.1007/s00412-023-00794-7 -
The bidirectional interplay between ncRNAs and methylation modifications in gastrointestinal tumors.International Journal of Biological... 2023The aberrant expression of methylation and ncRNAs, two crucial regulators of epigenetic modifications, has been widely demonstrated in cancer. The complex interplay... (Review)
Review
The aberrant expression of methylation and ncRNAs, two crucial regulators of epigenetic modifications, has been widely demonstrated in cancer. The complex interplay between them is essential in promoting malignant phenotype, poor prognosis, and drug resistance in GI tumors (including esophageal, gastric, colorectal, liver, and pancreatic cancers). Therefore, we summarize the interrelation process between ncRNAs and methylation modifications in GI tumors, including the detailed mechanism of methylation enzyme regulation of ncRNAs, the molecular mechanism of ncRNAs regulation of methylation modifications, and the correlation between the interactions between ncRNAs and methylation modifications and clinical features of tumors. Finally, we discuss the potential value of ncRNAs and methylation modifications in clinical diagnosis and therapy.
Topics: Humans; DNA Methylation; Gastrointestinal Neoplasms; Epigenesis, Genetic; RNA, Untranslated
PubMed: 37781524
DOI: 10.7150/ijbs.87028 -
Journal of Orthopaedic Surgery and... Oct 2023N6-methyl adenosine (m6A) is the most common reversible mRNA modification in eukaryotes implicated in key roles in various biological processes. The purpose of our...
BACKGROUND
N6-methyl adenosine (m6A) is the most common reversible mRNA modification in eukaryotes implicated in key roles in various biological processes. The purpose of our analysis was to examine the association of ankylosing spondylitis (AS) with m6A methylation.
METHOD
We obtained 72 samples from the data set GSE73754, including 52 AS patients and 20 healthy people. We divided the samples into two groups: the experimental group and the control group, and then observed the differences of 26 m6A related genes in the two groups. We also analyzed the correlation between different m6A genes. We used a random forest tree model to screen seven m6A signature genes associated with AS to evaluate its prevalence. Next, the samples were classified according to the m6a content and differential genes. Immune analysis, gene ontology, and KEGG enrichment analyses were performed. Finally, we scored each sample with m6a and analyzed the relationship between different samples and inflammation-related factors.
RESULTS AND CONCLUSION
In conclusion, we screened out AS-related genes and the nomogram showed that they were negatively correlated with the incidence of AS. And we found that AS may have some relationship with immunity. Our analysis results could provide further insights into the treatment of AS.
Topics: Humans; Methylation; Spondylitis, Ankylosing; Inflammation; Adenosine; Gene Ontology
PubMed: 37805597
DOI: 10.1186/s13018-023-04254-x -
Briefings in Functional Genomics Nov 2023Our understanding of the mechanisms that modulate gene expression in animals is strongly biased by studying a handful of model species that mainly belong to three...
Our understanding of the mechanisms that modulate gene expression in animals is strongly biased by studying a handful of model species that mainly belong to three groups: Insecta, Nematoda and Vertebrata. However, over half of the animal phyla belong to Spiralia, a morphologically and ecologically diverse animal clade with many species of economic and biomedical importance. Therefore, investigating genome regulation in this group is central to uncovering ancestral and derived features in genome functioning in animals, which can also be of significant societal impact. Here, we focus on five aspects of gene expression regulation to review our current knowledge of functional genomics in Spiralia. Although some fields, such as single-cell transcriptomics, are becoming more common, the study of chromatin accessibility, DNA methylation, histone post-translational modifications and genome architecture are still in their infancy. Recent efforts to generate chromosome-scale reference genome assemblies for greater species diversity and optimise state-of-the-art approaches for emerging spiralian research systems will address the existing knowledge gaps in functional genomics in this animal group.
Topics: Animals; Genomics; Chromatin; DNA Methylation; Gene Expression Profiling; Histones
PubMed: 37981859
DOI: 10.1093/bfgp/elad036 -
Journal of Autoimmunity Dec 2023Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of...
Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of autoantibodies. Decreased intestinal flora diversity and disruption of homeostasis have been proven to be associated with pathogenesis of SLE. In previous study, a clinical trial was conducted to verify the safety and effectiveness of fecal microbiota transplantation (FMT) in the treatment of SLE. To explore the mechanism of FMT in the treatment of SLE, we included 14 SLE patients participating in clinical trials, including 8 in responders group (Rs) and 6 in non-responders group (NRs), and collected peripheral blood DNA and serum. We found that the serum of S-adenosylmethionine (SAM), methylation group donor, was upregulated after FMT, accompanied by an increase in genome-wide DNA methylation level in Rs. We further showed that the methylation levels in promoter regions of Interferon-γ (IFN-γ), induced Helicase C Domain Containing Protein 1 (IFIH1), endoplasmic reticulum membrane protein complex 8 (EMC8), and Tripartite motif-containing protein 58 (TRIM58) increased after FMT treatment. On the contrary, there was no significant change in the methylation of IFIH1 promoter region in the NRs after FMT, and the methylation level of IFIH1 in the Rs was significantly higher than that in the NRs at week 0. We included 850 K methylation chip sequencing, combining previous data of metagenomic sequencing, and metabolomic sequencing for multi-omics analysis to discuss the relationship between flora-metabolite-methylation in FMT. Finally, we found that hexanoic acid treatment can up-regulate the global methylation of peripheral blood mononuclear cells in SLE patients. Overall, our results delineate changes in methylation level after FMT treatment of SLE and reveal possible mechanisms of FMT treatment in terms of the recovery of abnormal hypomethylation.
Topics: Humans; DNA Methylation; Fecal Microbiota Transplantation; Interferon-Induced Helicase, IFIH1; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic
PubMed: 37179169
DOI: 10.1016/j.jaut.2023.103047 -
European Journal of Cancer (Oxford,... Sep 2023Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and has a poor prognosis. Epigenetic modification has been shown to be deregulated during HCC... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and has a poor prognosis. Epigenetic modification has been shown to be deregulated during HCC development by dramatically impacting the differentiation, proliferation, and function of cells. One important epigenetic modification is DNA methylation during which methyl groups are added to cytosines without changing the DNA sequence itself. Studies found that methylated DNA markers can be specific for detection of HCC. On the basis of these findings, the utility of methylated DNA markers as novel biomarkers for early-stage HCC has been measured in blood, and indeed superior sensitivity and specificity have been found in several studies when compared to current surveillance methods. However, a variety of factors currently limit the immediate application of these exciting biomarkers. In this review, we provide a detailed rationalisation of the approach and basis for the use of methylation biomarkers for HCC detection and summarise recent studies on methylated DNA markers in HCC focusing on the importance of the aetiological cause of liver disease in the mechanisms leading to cancer.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; DNA Methylation; Genetic Markers; Biomarkers, Tumor
PubMed: 37473464
DOI: 10.1016/j.ejca.2023.112960 -
Proceedings of the National Academy of... Aug 2023Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by...
Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes. A gradient of TF expression changes forms a basis for the subtypes of abnormal DNA methylation, termed CpG-island promoter DNA methylation phenotypes (CIMPs), in CRCs and other cancers. CIMP is tightly correlated with cancer-specific hypermethylation at enhancers, which we term CpG-enhancer methylation phenotype (CEMP). Coordinated promoter and enhancer methylation appears to be driven by downregulation of TFs with common binding sites at the hypermethylated enhancers and promoters. The altered expression of TFs related to hypermethylator subtypes occurs early during CRC development, detectable in premalignant adenomas. TF-based profiling further identifies patients with worse overall survival. Importantly, altered expression of these TFs discriminates the transcriptome-based consensus molecular subtypes (CMS), thus providing a common basis for CIMP and CMS subtypes.
Topics: Humans; Transcription Factors; Gene Expression Regulation; DNA Methylation; Precancerous Conditions; Colorectal Neoplasms; Epigenesis, Genetic
PubMed: 37487069
DOI: 10.1073/pnas.2301536120 -
Epigenetics Dec 2023African American (AA) men have the highest incidence and mortality rate from Prostate cancer (PCa) than any other racial/ethnic group. To date, PCa genomic studies have...
African American (AA) men have the highest incidence and mortality rate from Prostate cancer (PCa) than any other racial/ethnic group. To date, PCa genomic studies have largely under-represented tumour samples from AA men. We measured genome-wide DNA methylation in benign and tumor prostate tissues from AA men using the Illumina Infunium 850 K EPIC array. mRNA expression database from a subset of the AA biospecimen were used to assess correlation of transcriptome and methylation datasets. Genome-wide methylation analysis identified 11,460 probes that were significant (p < 0.01) and differentially methylated in AA PCa compared to normal prostate tissues and showed significant (p < 0.01) inverse-correlation with mRNA expression. Ingenuity pathway analysis and Gene Ontology analysis in our AA dataset compared with TCGA dataset showed similarities in methylation patterns: top candidate genes with significant hypermethylation and corresponding down-regulated gene expression were associated with biological pathways in hemidesmosome assembly, mammary gland development, epidermis development, hormone biosynthesis, and cell communication. In addition, top candidate genes with significant hypomethylation and corresponding up-regulated gene expression were associated with biological pathways in macrophage differentiation, cAMP-dependent protein kinase activity, protein destabilization, transcription co-repression, and fatty acid biosynthesis. In contrast, differences in genome-wide methylation in our AA dataset compared with TCGA dataset were enriched for genes in steroid signalling, immune signalling, chromatin structure remodelling and RNA processing. Overall, differential methylation of 3, 3, 1, 7, 2C, 2, 2, 292, 2, 1, and 6 were significant and uniquely associated with PCa progression in our AA cohort.
Topics: Male; Humans; DNA Methylation; Transcriptome; Black or African American; Epigenomics; Prostatic Neoplasms; RNA, Messenger; Gene Expression Regulation, Neoplastic; CpG Islands; Carrier Proteins; Nerve Tissue Proteins
PubMed: 37279148
DOI: 10.1080/15592294.2023.2180585 -
Molecular Biology of the Cell Jul 2024Cilia are highly complex motile, sensory, and secretory organelles that contain perhaps 1000 or more distinct protein components, many of which are subject to various...
Cilia are highly complex motile, sensory, and secretory organelles that contain perhaps 1000 or more distinct protein components, many of which are subject to various posttranslational modifications such as phosphorylation, N-terminal acetylation, and proteolytic processing. Another common modification is the addition of one or more methyl groups to the side chains of arginine and lysine residues. These tunable additions delocalize the side-chain charge, decrease hydrogen bond capacity, and increase both bulk and hydrophobicity. Methylation is usually mediated by S-adenosylmethionine (SAM)-dependent methyltransferases and reversed by demethylases. Previous studies have identified several ciliary proteins that are subject to methylation including axonemal dynein heavy chains that are modified by a cytosolic methyltransferase. Here, we have performed an extensive proteomic analysis of multiple independently derived cilia samples to assess the potential for SAM metabolism and the extent of methylation in these organelles. We find that cilia contain all the enzymes needed for generation of the SAM methyl donor and recycling of the S-adenosylhomocysteine and tetrahydrofolate byproducts. In addition, we find that at least 155 distinct ciliary proteins are methylated, in some cases at multiple sites. These data provide a comprehensive resource for studying the consequences of methyl marks on ciliary biology.
Topics: Cilia; S-Adenosylmethionine; Methylation; Protein Processing, Post-Translational; Proteomics; Animals; Humans; Methyltransferases; S-Adenosylhomocysteine; Epigenome
PubMed: 38696262
DOI: 10.1091/mbc.E24-03-0130