-
British Journal of Cancer Aug 2023Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist... (Review)
Review
Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on mA RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides mA RNA methylation. In this review, we focus on several important RNA modifications including mA, mC, mG, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
Topics: Humans; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA; Neoplasms; Methylation
PubMed: 37095185
DOI: 10.1038/s41416-023-02275-1 -
European Journal of Internal Medicine Aug 2023Epigenetics is a rapidly growing field of biology that studies the changes in gene expression that are not due to alterations in the DNA sequence but rather the chemical... (Review)
Review
Epigenetics is a rapidly growing field of biology that studies the changes in gene expression that are not due to alterations in the DNA sequence but rather the chemical modifications of DNA and its associated proteins. Epigenetic mechanisms can profoundly influence gene expression, cell differentiation, tissue development, and disease susceptibility. Understanding epigenetic changes is essential to elucidate the mechanisms underlying the increasingly recognized role of environmental and lifestyle factors in health and disease and the intergenerational transmission of phenotypes. Recent studies suggest epigenetics may be critical in various diseases, from cardiovascular disease and cancer to neurodevelopmental and neurodegenerative disorders. Epigenetic modifications are potentially reversible and could provide new therapeutic avenues for treating these diseases using epigenetic modulators. Moreover, epigenetics provide insight into disease pathogenesis and biomarkers for disease diagnosis and risk stratification. Nevertheless, epigenetic interventions have the potential for unintended consequences and may potentially lead to increased risks of unexpected outcomes, such as adverse drug reactions, developmental abnormalities, and cancer. Therefore, rigorous studies are essential to minimize the risks associated with epigenetic therapies and to develop safe and effective interventions for improving human health. This article provides a synthetic and historical view of the origin of epigenetics and some of the most relevant achievements.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Neoplasms
PubMed: 37277249
DOI: 10.1016/j.ejim.2023.05.036 -
Journal of Translational Medicine Sep 2023Intracranial aneurysms (IAs) pose a significant and intricate challenge. Elucidating the interplay between DNA methylation and IA pathogenesis is paramount to identify...
DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data.
BACKGROUND
Intracranial aneurysms (IAs) pose a significant and intricate challenge. Elucidating the interplay between DNA methylation and IA pathogenesis is paramount to identify potential biomarkers and therapeutic interventions.
METHODS
We employed a comprehensive bioinformatics investigation of DNA methylation in IA, utilizing a transcriptomics-based methodology that encompassed 100 machine learning algorithms, genome-wide association studies (GWAS), Mendelian randomization (MR), and summary-data-based Mendelian randomization (SMR). Our sophisticated analytical strategy allowed for a systematic assessment of differentially methylated genes and their implications on the onset, progression, and rupture of IA.
RESULTS
We identified DNA methylation-related genes (MRGs) and associated molecular pathways, and the MR and SMR analyses provided evidence for potential causal links between the observed DNA methylation events and IA predisposition.
CONCLUSION
These insights not only augment our understanding of the molecular underpinnings of IA but also underscore potential novel biomarkers and therapeutic avenues. Although our study faces inherent limitations and hurdles, it represents a groundbreaking initiative in deciphering the intricate relationship between genetic, epigenetic, and environmental factors implicated in IA pathogenesis.
Topics: Humans; Multiomics; Intracranial Aneurysm; DNA Methylation; Epigenome; Genome-Wide Association Study; Mendelian Randomization Analysis; Machine Learning
PubMed: 37742034
DOI: 10.1186/s12967-023-04512-w -
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 -
Cancer Research Aug 2023Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression...
UNLABELLED
Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation.
SIGNIFICANCE
Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
Topics: Humans; DNA Methylation; DNA Transposable Elements; Transcriptional Activation; Sequence Analysis, RNA; Neoplasms
PubMed: 37249603
DOI: 10.1158/0008-5472.CAN-22-3485 -
Gut Microbes Dec 2023Individuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of...
Individuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD. Moreover, we assessed whether plasma metabolite profiles altered by FMT relate to changes in liver DNA methylation. Twenty-one individuals with NAFLD underwent three 8-weekly vegan allogenic donor ( = 10) or autologous ( = 11) FMTs. We obtained hepatic DNA methylation profiles from paired liver biopsies of study participants before and after FMTs. We applied a multi-omics machine learning approach to identify changes in the gut microbiome, peripheral blood metabolome and liver DNA methylome, and analyzed cross-omics correlations. Vegan allogenic donor FMT compared to autologous FMT induced distinct differential changes in I) gut microbiota profiles, including increased abundance of and potential probiotic ; II) plasma metabolites, including altered levels of phenylacetylcarnitine (PAC) and phenylacetylglutamine (PAG) both from gut-derived phenylacetic acid, and of several choline-derived long-chain acylcholines; and III) hepatic DNA methylation profiles, most importantly in Threonyl-TRNA Synthetase 1 ( and Zinc finger protein 57 (. Multi-omics analysis showed that and __170 positively correlated with both PAC and PAG. negatively correlated with DNA methylation of cg16885113 in . Alterations in gut microbiota composition by FMT caused widespread changes in plasma metabolites (e.g. PAC, PAG, and choline-derived metabolites) and liver DNA methylation profiles in individuals with NAFLD. These results indicate that FMTs might induce metaorganismal pathway changes, from the gut bacteria to the liver.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Fecal Microbiota Transplantation; DNA Methylation; Multiomics; Gastrointestinal Microbiome; Choline
PubMed: 37317027
DOI: 10.1080/19490976.2023.2223330 -
Clinical and Translational Medicine Sep 2023The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being...
BACKGROUND
The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation and fusion are driven by oxidative phosphorylation.
METHODS
By polymerase chain reaction as well as Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, the mouse precranial osteoblast cell line MC3T3-E1 and the mouse monocyte macrophage leukaemia cell line RAW264.7, and expression of related genes during osteogenic differentiation and osteoclast differentiation. Using gene overexpression (lentivirus) and loss-of-function approach (CRISPR/Cas9-mediated knockout) in vitro, we examined whether CARM1 regulates osteogenic differentiation and osteoblast differentiation by metabolic regulation. Transcriptomic assays and metabolomic assays were used to find the mechanism of action of CARM1. Furthermore, in vitro methylation assays were applied to clarify the arginine methylation site of PPP1CA by CARM1.
RESULTS
We discovered that CARM1 reprogrammed glucose metabolism in osteoblasts and osteoclasts from oxidative phosphorylation to aerobic glycolysis, thereby promoting osteogenic differentiation and inhibiting osteoclastic differentiation. In vivo experiments revealed that CARM1 significantly decreased bone loss in osteoporosis model mice. Mechanistically, CARM1 methylated R23 of PPP1CA, affected the dephosphorylation of AKT-T450 and AMPK-T172, and increased the activities of phosphofructokinase-1 and pructose-2,6-biphosphatase3, causing an up-regulation of glycolytic flux. At the same time, as a transcriptional coactivator, CARM1 regulated the expression of pyruvate dehydrogenase kinase 3, which resulted in the inhibition of pyruvate dehydrogenase activity and inhibition of the tricarboxylic acid cycle, leading to a subsequent decrease in the flux of oxidative phosphorylation.
CONCLUSIONS
These findings reveal for the first time the mechanism by which CARM1 affects both osteogenesis and osteoclast differentiation through metabolic regulation, which may represent a new feasible treatment strategy for osteoporosis.
Topics: Animals; Mice; Osteogenesis; Methylation; Cell Differentiation; Arginine; Glucose
PubMed: 37649137
DOI: 10.1002/ctm2.1369 -
Advanced Science (Weinheim,... Dec 2023Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for...
Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis-associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis-based antitumor therapy.
Topics: Humans; Ferroptosis; Methylation; Protein-Arginine N-Methyltransferases; Colorectal Neoplasms
PubMed: 37946697
DOI: 10.1002/advs.202303484 -
Biochimica Et Biophysica Acta. Gene... Dec 2023Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and... (Review)
Review
Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.
Topics: Humans; Histones; Lysine; Histone Demethylases; Protein Processing, Post-Translational; Methylation
PubMed: 37572976
DOI: 10.1016/j.bbagrm.2023.194968 -
Epigenetics Dec 2023DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes...
DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes in humans. On top of that, the DNA methylome undergoes profound changes in cancer and other disorders. However, large-scale and population-based studies are limited by high costs and the need for considerable expertise in data analysis for whole-genome bisulphite-sequencing methodologies. Following the success of the EPIC DNA methylation microarray, the newly developed Infinium HumanMethylationEPIC version 2.0 (900K EPIC v2) is now available. This new array contains more than 900,000 CpG probes covering the human genome and excluding masked probes from the previous version. The 900K EPIC v2 microarray adds more than 200,000 probes covering extra DNA cis-regulatory regions such as enhancers, super-enhancers and CTCF binding regions. Herein, we have technically and biologically validated the new methylation array to show its high reproducibility and consistency among technical replicates and with DNA extracted from FFPE tissue. In addition, we have hybridized primary normal and tumoural tissues and cancer cell lines from different sources and tested the robustness of the 900K EPIC v2 microarray when analysing the different DNA methylation profiles. The validation highlights the improvements offered by the new array and demonstrates the versatility of this updated tool for characterizing the DNA methylome in human health and disease.
Topics: Humans; DNA Methylation; Epigenome; Reproducibility of Results; Microarray Analysis; Cell Line
PubMed: 36871255
DOI: 10.1080/15592294.2023.2185742