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Cold Spring Harbor Perspectives in... May 2017Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to... (Review)
Review
Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; DNA Demethylation; Decitabine; Humans; Neoplasms; Tumor Microenvironment
PubMed: 28159832
DOI: 10.1101/cshperspect.a026948 -
The New England Journal of Medicine Oct 2018
Topics: Animals; Benzazepines; Cell Line, Tumor; Child; Demethylation; Gene Expression; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Models, Animal; Neuroblastoma; Pyrimidines
PubMed: 30304660
DOI: 10.1056/NEJMcibr1806782 -
Nature Reviews. Rheumatology Oct 2018
Topics: Animals; DNA Demethylation; DNA Methylation; Epigenesis, Genetic; Epigenomics; Mice
PubMed: 30206374
DOI: 10.1038/s41584-018-0089-2 -
European Heart Journal May 2023
Topics: Humans; RNA, Antisense; RNA, Long Noncoding; Ventricular Remodeling; Pericardium; Demethylation; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36928295
DOI: 10.1093/eurheartj/ehad058 -
Cell Death & Disease Jun 2023Tau hyperphosphorylation in hippocampal neurons has an important pathogenetic role in the development of diabetic cognitive dysfunction. N-methyladenosine (mA)...
High glucose induces tau hyperphosphorylation in hippocampal neurons via inhibition of ALKBH5-mediated Dgkh mA demethylation: a potential mechanism for diabetic cognitive dysfunction.
Tau hyperphosphorylation in hippocampal neurons has an important pathogenetic role in the development of diabetic cognitive dysfunction. N-methyladenosine (mA) methylation is the most common modification of eukaryotic mRNA and is involved in regulating diverse biological processes. However, the role of mA alteration in tau hyperphosphorylation of hippocampus neurons has not been reported. We found lower ALKBH5 expression in the hippocampus of diabetic rats and in HN-h cells with high-glucose intervention, accompanied by tau hyperphosphorylation. ALKBH5 overexpression significantly reversed tau hyperphosphorylation in high-glucose-stimulated HN-h cells. Furthermore, we found and confirmed by mA-mRNA epitope transcriptome microarray and transcriptome RNA sequencing coupled with methylated RNA immunoprecipitation that ALKBH5 regulates the mA modification of Dgkh mRNA. High glucose inhibited the demethylation modification of Dgkh by ALKBH5, resulting in decreases in Dgkh mRNA and protein levels. Overexpression of Dgkh reversed tau hyperphosphorylation in HN-h cells after high-glucose stimulation. Overexpression of Dgkh by adenovirus suspension injection into the bilateral hippocampus of diabetic rats significantly ameliorated tau hyperphosphorylation and diabetic cognitive dysfunction. In addition, ALKBH5 targeted Dgkh to activate PKC-α, leading to tau hyperphosphorylation under high-glucose conditions. The results of this study reveal that high glucose suppresses the demethylation modification of Dgkh by ALKBH5, which downregulates Dgkh and leads to tau hyperphosphorylation through activation of PKC-α in hippocampal neurons. These findings may indicate a new mechanism and a novel therapeutic target for diabetic cognitive dysfunction.
Topics: Animals; Rats; Diabetes Mellitus, Experimental; Neurons; RNA, Messenger; Cognitive Dysfunction; Hippocampus; Demethylation; Glucose
PubMed: 37385994
DOI: 10.1038/s41419-023-05909-7 -
Essays in Biochemistry Dec 2019DNA methylation is an essential DNA modification that plays a crucial role in genome regulation during differentiation and development, and is disrupted in a range of... (Review)
Review
DNA methylation is an essential DNA modification that plays a crucial role in genome regulation during differentiation and development, and is disrupted in a range of disease states. The recent development of CRISPR/catalytically dead CRISPR/Cas9 (dCas9)-based targeted DNA methylation editing tools has enabled new insights into the roles and functional relevance of this modification, including its importance at regulatory regions and the role of aberrant methylation in various diseases. However, while these tools are advancing our ability to understand and manipulate this regulatory layer of the genome, they still possess a variety of limitations in efficacy, implementation, and targeting specificity. Effective targeted DNA methylation editing will continue to advance our fundamental understanding of the role of this modification in different genomic and cellular contexts, and further improvements may enable more accurate disease modeling and possible future treatments. In this review, we discuss strategies, considerations, and future directions for targeted DNA methylation editing.
Topics: Animals; Bacterial Proteins; CRISPR-Associated Protein 9; CRISPR-Cas Systems; DNA; DNA Demethylation; DNA Methylation; Epigenomics; Gene Editing; Humans; Streptococcus pyogenes
PubMed: 31724704
DOI: 10.1042/EBC20190029 -
Journal of Genetics and Genomics = Yi... Aug 2022Plants recognize microbe-associated molecular patterns (MAMPs) to activate immune responses and defense priming to defend against pathogen infections. Transcriptional...
Plants recognize microbe-associated molecular patterns (MAMPs) to activate immune responses and defense priming to defend against pathogen infections. Transcriptional regulation of gene expression is crucial for plant immunity and is mediated by multiple factors, including DNA methylation. However, it remains unknown whether and how DNA demethylation contributes to immune responses in MAMP-triggered immunity. Here, we report that active DNA demethylation is required for MAMP-triggered immunity to bacterial pathogens. The rdd-2 triple mutant carrying mutations in ROS1, DML2, and DML3 that encode DNA glycosylases, which are key DNA demethylation enzymes, exhibits compromised immune responses triggered by the MAMPs flg22 and elf18. Genome-wide methylome analysis reveals that flg22 induces rapid and specific DNA demethylation in an RDD-dependent manner. The expression levels of salicylic acid signaling-related and phytoalexin biosynthesis-related genes are tightly associated with the flg22-induced promoter demethylation. The compromised accumulation of priming compounds and antimicrobial metabolites ultimately leads to a defense priming defect in the rdd-2 mutant. Our results reveal the critical role of active DNA demethylation in the MAMP-triggered immune response and provide unique insight into the molecular mechanism of flg22-modulated DNA demethylation.
Topics: Arabidopsis; Arabidopsis Proteins; DNA Demethylation; DNA Glycosylases; Gene Expression Regulation, Plant; Plant Diseases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins
PubMed: 35288370
DOI: 10.1016/j.jgg.2022.02.021 -
Molecular Biology Reports Sep 2023DNA methylation and demethylation are widely acknowledged epigenetic phenomena which can cause heritable and phenotypic changes in functional genes without changing the... (Review)
Review
DNA methylation and demethylation are widely acknowledged epigenetic phenomena which can cause heritable and phenotypic changes in functional genes without changing the DNA sequence. They can thus affect phenotype formation in medicinal plants. However, a comprehensive review of the literature summarizing current research trends in this field is lacking. Thus, this review aims to provide an up-to-date summary of current methods for the detection of 5-mC DNA methylation, identification and analysis of DNA methyltransferases and demethyltransferases, and regulation of DNA methylation in medicinal plants. The data showed that polyploidy and environmental changes can affect DNA methylation levels in medicinal plants. Changes in DNA methylation can thus regulate plant morphogenesis, growth and development, and formation of secondary metabolites. Future research is required to explore the mechanisms by which DNA methylation regulates the accumulation of secondary metabolites in medicinal plants.
Topics: Plants, Medicinal; DNA Methylation; DNA Modification Methylases; Epigenomics; Demethylation
PubMed: 37480509
DOI: 10.1007/s11033-023-08618-8 -
Clinical and Translational Medicine Sep 2023Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and...
BACKGROUND
Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and mechanistic aspects of CDO1 inactivation in BC are poorly understood, and the diagnostic significance of serum CDO1 methylation remains unclear.
METHODS
We performed bioinformatics analysis of publicly available databases and employed MassARRAY EpiTYPER methylation sequencing technology to identify differentially methylated sites in the CDO1 promoter of BC tissues compared to normal adjacent tissues (NATs). Subsequently, we developed a MethyLight assay using specific primers and probes for these CpG sites to detect the percentage of methylated reference (PMR) of the CDO1 promoter. Furthermore, both LentiCRISPR/dCas9-Tet1CD-based CDO1-targeted demethylation system and CDO1 overexpression strategy were utilized to detect the function and underlying mechanism of CDO1 in BC. Finally, the early diagnostic value of CDO1 as a methylation biomarker in BC serum was evaluated.
RESULTS
CDO1 promoter was hypermethylated in BC tissues, which was related to poor prognosis (p < .05). The CRISPR/dCas9-based targeted demethylation system significantly reduced the PMR of CDO1 promotor and increased CDO1 expression in BC cells. Consequently, this leads to suppression of cell proliferation, migration and invasion. Additionally, we found that CDO1 exerted a tumour suppressor effect by inhibiting the cell cycle, promoting cell apoptosis and ferroptosis. Furthermore, we employed the MethyLight to detect CDO1 PMR in BC serum, and we discovered that serum CDO1 methylation was an effective non-invasive biomarker for early diagnosis of BC.
CONCLUSIONS
CDO1 is hypermethylated and acts as a tumour suppressor gene in BC. Epigenetic editing of abnormal CDO1 methylation could have a crucial role in the clinical treatment and prognosis of BC. Additionally, serum CDO1 methylation holds promise as a valuable biomarker for the early diagnosis and management of BC.
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Cysteine Dioxygenase; Apoptosis; Cell Cycle; Demethylation; Neoplasms
PubMed: 37740473
DOI: 10.1002/ctm2.1423 -
Cancer Research Jul 2021RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases... (Review)
Review
RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1-2, YTHDF1-3, IGF2BP1-3, and SND1 (readers). These RNA mA modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA mA modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA mA modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA mA modification protein expression or RNA mA modification protein-induced resistance to cancer therapy.
Topics: Adenosine; Animals; Demethylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Methylation; Neoplasms; RNA
PubMed: 34228629
DOI: 10.1158/0008-5472.CAN-20-4107