De novo methyltransferases: Potential players in diseases and new directions for targeted therapy

Ponne, Saravanaraman; Selvam, Murugan; Ashok, Cheemala; Srijyothi, Loudu; Baluchamy, Sudhakar

doi:10.1016/j.biochi.2020.07.004

Cited by 20 publications

(12 citation statements)

References 199 publications

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“…Instead of changing the nucleotide sequence, DNA methylation directly modifies genomic DNA and affects gene expression. The regulation of the DNMTs' activity and expression can directly affect the genomic DNA methylation level and target gene expression [ 22 , 23 ]. In our research, TGF- β 1 was observed to markedly suppress the global DNMT activity and down-regulate the mRNA and protein expressions of DNMT1 and DNMT3a in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces Interlukin-11 Expression and Pro-Fibrotic Effect by DNA Demethylation in Subconjunctival Fibroblasts

Lü

2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To assess Interlukin-11 (IL11) expression in the tears of patients after filtration surgery and to find out its pro-transdifferentiational and pro-fibrotic functions and mechanisms on subconjunctival human Tenon’s capsule fibroblasts (HTFs) induced by transforming growth factor beta1 (TGF-β1). Methods. Tears were collected from glaucoma patients with or without filtration surgery. The expression of IL11 in tears was examined by enzyme-linked immunosorbent assay. Primary HTFs were prepared as an expansion culture of human Tenon’s explants from patients undergoing cataract surgery. TGF-β1 and IL11 were used to stimulate the cultured HTFs. Quantitative RT-PCR and western blot analyzed the roles of TGF-β1 in IL11 and DNA methyltransferase (DNMT) expression and the effects of IL11 on collagen-1A1 and α-smooth muscle actin expression. The effects of IL11 on human HTFs’ migration were tested via the scratch-wound assay. MassARRAY platform of Sequenom was applied for analyzing the quantitative methylation of the IL11 promoter region. Result. Our data presented significantly high levels of IL11 in the tears of patients who underwent filtration surgery with uncontrolled intraocular pressure (IOP) compared with those who underwent filtration surgery with controlled IOP. The up-regulation of IL11 was related to TGF-β1. We also found that TGF-β induced IL11 up-regulation in the HTFs, which activates the HTFs and enhanced the translation of the pro-fibrotic protein expression. This is correlated with inhibiting the activity and expression of DNMTs and demethylating the IL11 promoter. Therefore, IL11 may be an ideal target to be regulated to control the filtering pathway scar formation.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces Interlukin-11 Expression and Pro-Fibrotic Effect by DNA Demethylation in Subconjunctival Fibroblasts

Lü

2022

Evidence-Based Complementary and Alternative Medicine

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“…Interaction of hsa-miR-29c with both BACE1 and DNMT3 was experimentally confirmed in CSF or blood samples [42,44]. De novo methyltransferase DNMT3 established methylation patterns on DNA and had an important role in genome imprinting [80]. Potential use of hsa-miR-29c as an AD circulating biomarker was further confirmed using RNA deep sequencing [81].…”

Section: Discussionmentioning

confidence: 87%

Systematic Search for Novel Circulating Biomarkers Associated with Extracellular Vesicles in Alzheimer’s Disease: Combining Literature Screening and Database Mining Approaches

Vogrinc

Goričar

Kunej

et al. 2021

JPM

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miRNAs play an important role in neurodegenerative diseases. Many miRNA-target gene interactions (MTI) have been experimentally confirmed and associated with Alzheimer’s disease (AD). miRNAs may also be contained within extracellular vesicles (EVs), mediators of cellular communication and a potential source of circulating biomarkers in body fluids. Therefore, EV-associated miRNAs (EV-miRNAs) in peripheral blood could support earlier and less invasive AD diagnostics. We aimed to prioritize EV-related miRNA with AD-related genes and to identify the most promising candidates for novel AD biomarkers. A list of unique EV-miRNAs from the literature was combined with a known set of AD risk genes and enriched for MTI. Additionally, miRNAs associated with the AD phenotype were combined with all known target genes in MTI enrichment. Expression in different sample types was analyzed to identify AD-associated miRNAs with the greatest potential as AD circulating biomarkers. Four common MTI were observed between EV-miRNAs and AD-associated miRNAs: hsa-miR-375–APH1B, hsa-miR-107–CDC42SE2, hsa-miR-375–CELF2, and hsa-miR-107–IL6. An additional 61 out of 169 unique miRNAs (36.1%) and seven out of 84 unique MTI (8.3%), observed in the body fluids of AD patients, were proposed as very strong AD-circulating biomarker candidates. Our analysis summarized several potential novel AD biomarkers, but further studies are needed to evaluate their potential in clinical practice.

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“…Although both isoforms have the PWWP, ADD domain, and the identical catalytic domain, a difference in DNA methylation activity is observed; with DNMT3A1 having a higher DNA-binding and DNA methylation activity compared to DNMT3A2 ( 62 ). Moreover, DNMT3A1 also shows a higher affinity for heterochromatin, while DNMT3A2 has more affinity for euchromatin ( 51 , 52 ). For DNMT3B, more than forty different isoforms have been reported and are known to be expressed in a tissue specific manner.…”

Section: Dna Methylationmentioning

confidence: 99%

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Muylaert

Hemelrijck²,

Maes³

et al. 2022

Front. Oncol.

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Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.

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De novo methyltransferases: Potential players in diseases and new directions for targeted therapy

Cited by 20 publications

References 199 publications

TGF-β1 Induces Interlukin-11 Expression and Pro-Fibrotic Effect by DNA Demethylation in Subconjunctival Fibroblasts

TGF-β1 Induces Interlukin-11 Expression and Pro-Fibrotic Effect by DNA Demethylation in Subconjunctival Fibroblasts

Systematic Search for Novel Circulating Biomarkers Associated with Extracellular Vesicles in Alzheimer’s Disease: Combining Literature Screening and Database Mining Approaches

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

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