-
Signal Transduction and Targeted Therapy Sep 2023The mineral dust-induced gene (MDIG) comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation (H3K9me3). Previous studies...
The mineral dust-induced gene (MDIG) comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation (H3K9me3). Previous studies have indicated the significance of MDIG in promoting cell proliferation by modulating cell-cycle transition. However, its involvement in liver regeneration has not been extensively investigated. In this study, we generated mice with liver-specific knockout of MDIG and applied partial hepatectomy or carbon tetrachloride mouse models to investigate the biological contribution of MDIG in liver regeneration. The MDIG levels showed initial upregulation followed by downregulation as the recovery progressed. Genetic MDIG deficiency resulted in dramatically impaired liver regeneration and delayed cell cycle progression. However, the MDIG-deleted liver was eventually restored over a long latency. RNA-seq analysis revealed Myc as a crucial effector downstream of MDIG. However, ATAC-seq identified the reduced chromatin accessibility of OTX2 locus in MDIG-ablated regenerating liver, with unaltered chromatin accessibility of Myc locus. Mechanistically, MDIG altered chromatin accessibility to allow transcription by demethylating H3K9me3 at the OTX2 promoter region. As a consequence, the transcription factor OTX2 binding at the Myc promoter region was decreased in MDIG-deficient hepatocytes, which in turn repressed Myc expression. Reciprocally, Myc enhanced MDIG expression by regulating MDIG promoter activity, forming a positive feedback loop to sustain hepatocyte proliferation. Altogether, our results prove the essential role of MDIG in facilitating liver regeneration via regulating histone methylation to alter chromatin accessibility and provide valuable insights into the epi-transcriptomic regulation during liver regeneration.
Topics: Animals; Mice; Liver Regeneration; Cell Proliferation; Chromatin; Liver; Demethylation
PubMed: 37709738
DOI: 10.1038/s41392-023-01575-5 -
The New England Journal of Medicine May 2022Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated.
BACKGROUND
Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated.
METHODS
We examined the effect of hypomethylating agents on , a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable expression were used to study the relationship between methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for expression.
RESULTS
up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of expression.
CONCLUSIONS
By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
Topics: Antineoplastic Agents; Clustered Regularly Interspaced Short Palindromic Repeats; Demethylation; Humans; Myelodysplastic Syndromes; Neoplasms; Oncogenes; Transcription Factors; Up-Regulation
PubMed: 35613022
DOI: 10.1056/NEJMoa2119771 -
Journal of Molecular Medicine (Berlin,... Jul 2017In mammals, the unicellular zygote starts the process of embryogenesis and differentiates into all types of somatic cells, including both fetal and extraembryonic... (Review)
Review
In mammals, the unicellular zygote starts the process of embryogenesis and differentiates into all types of somatic cells, including both fetal and extraembryonic lineages-in a highly organized manner to eventually give rise to an entire multicellular organism comprising more than 200 different tissue types. This feature is referred to as totipotency. Upon fertilization, oocyte maternal factors epigenetically reprogram the genomes of the terminally differentiated oocyte and spermatozoon and turn the zygote into a totipotent cell. Today, we still do not fully understand the molecular properties of totipotency. In this review, we discuss recent findings on the molecular signature and mechanism of transcriptional regulation networks in the totipotent mouse embryo.
Topics: Animals; DNA Demethylation; Embryo, Mammalian; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Histone Code; Mice; Octamer Transcription Factor-3; Transcriptional Activation; Zygote
PubMed: 28102431
DOI: 10.1007/s00109-017-1509-5 -
Nucleic Acids Research Mar 2024Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic....
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
Topics: Humans; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Demethylation; DNA Methylation; Histones; Melanoma; Promyelocytic Leukemia Protein; RNA; Transcription Factors; Antigens, Nuclear; Autoantigens; Eye Neoplasms
PubMed: 38118002
DOI: 10.1093/nar/gkad1193 -
Cancer Cell Feb 2019Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine... (Review)
Review
Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear. Here, we discuss catalytic-dependent and -independent functions of UTX and its partners MLL3 and MLL4 as part of the COMPASS family during development and in oncogenesis.
Topics: Animals; DNA-Binding Proteins; Demethylation; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Mutation; Neoplasms; Phenotype; Signal Transduction; Tumor Suppressor Proteins
PubMed: 30753822
DOI: 10.1016/j.ccell.2019.01.001 -
Oncotarget Oct 2016Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and... (Review)
Review
Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Currently, there are nine known members of the protein arginine methyltransferase (PRMT) family, but only one arginine demethylase has been identified, namely the Jumonji domain-containing 6 (JMJD6). Although its demethylase activity was initially challenged, its dual activity as an arginine demethylase and a lysine hydroxylase is now recognized. Interestingly, a growing number of substrates for arginine methylation and demethylation play key roles in tumorigenesis. Though alterations in the sequence of these enzymes have not been identified in cancer, their overexpression is associated with various cancers, suggesting that they could constitute targets for therapeutic strategies. In this review, we present the recent knowledge of the involvement of PRMTs and JMJD6 in tumorigenesis.
Topics: Arginine; Demethylation; Humans; Jumonji Domain-Containing Histone Demethylases; Methylation; Neoplasms; Protein Processing, Post-Translational
PubMed: 27556302
DOI: 10.18632/oncotarget.11376 -
Redox Biology Aug 2023There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for...
There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for cancer treatments and cardiac repair, with demethylation emerging as a common factor in these candidate lists. As DNA methyltransferase 1 (DNMT1) majorly responds to methylation, a natural compound library is screened, identifying dioscin as a novel agent targeted at DNMT1, widely used for heart diseases. Dioscin was found to reduce DNMT activities and inhibits growth in breast cancer cells. Combined with analyses of RNA-seq and MeDIP-seq, the promoters of antioxidant genes were demethylated after dioscin, recruiting NRF2 and elevating their expression. In Nrf2 knockout mice, the cardiac protection role of dioscin was blocked by Nrf2-loss. Furthermore, in tumour-bearing mice with hypertrophy, dioscin was observed to inhibit tumour growth and alleviate cardiac injury simultaneously. This study is the first to identify dioscin as a novel demethylation agent with dual functions of anti-cancer and cardio-protection.
Topics: Mice; Animals; Recovery of Function; NF-E2-Related Factor 2; Neoplasms; Demethylation; DNA Methylation
PubMed: 37343447
DOI: 10.1016/j.redox.2023.102785 -
Journal of Advanced Research Dec 2023Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial... (Review)
Review
BACKGROUND
Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial disease. Diabetic foot ulcers (DFU) are difficult to heal, which makes patients susceptible to infections and can ultimately conduce to limb amputation or even death in severe cases. An increasing number of studies have found that epigenetic alterations are strongly associated with poor wound healing in diabetes.
AIM OF REVIEW
This work provides significant insights into the development of therapeutics for improving chronic diabetic wound healing, particularly by targeting and regulating DNA methylation and demethylation in DFU. Key scientific concepts of review: DNA methylation and demethylation play an important part in diabetic wound healing, via regulating corresponding signaling pathways in different breeds of cells, including macrophages, vascular endothelial cells and keratinocytes. In this review, we describe the four main phases of wound healing and their abnormality in diabetic patients. Furthermore, we provided an in-depth summary and discussion on how DNA methylation and demethylation regulate diabetic wound healing in different types of cells; and gave a brief summary on recent advances in applying cellular reprogramming techniques for improving diabetic wound healing.
Topics: Humans; Diabetic Foot; DNA Methylation; Endothelial Cells; Wound Healing; Demethylation; Diabetes Mellitus
PubMed: 36706989
DOI: 10.1016/j.jare.2023.01.009 -
Scientific Reports Apr 2023Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene...
Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1 versus DNMT1 status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice bearing HCT116 DNMT1 xenograft and bladder PDX tumors. DNMT1 gene deletion occurred in ~ 9% human colon cancers and other cancer types at varying degrees. Decitabine and azacitidine demethylated CDKN2A/CDKN2B genes in DNMT1 and DNMT1 conditions and increased histone-H3 acetylation with re-expression of p16/p15 in DNMT1 state. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.
Topics: Humans; Mice; Animals; Decitabine; DNA (Cytosine-5-)-Methyltransferases; DNA (Cytosine-5-)-Methyltransferase 1; Azacitidine; DNA Damage; Demethylation; DNA; DNA Methylation; Cell Line, Tumor
PubMed: 37045940
DOI: 10.1038/s41598-023-32509-4 -
RNA Biology Sep 2017Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by... (Review)
Review
Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by modified tRNA-bases or silencing and reactivation of genes by methylation and demethylation of cytosine in promoter regions. Especially dynamic methylation of adenine and cytosine is essential for cells to adapt to their environment or for the development of complex organisms from a single cell. Errors in the cytosine methylation pattern are associated with most types of cancer and bacteria use methylated nucleobases to resist antibiotics. This Point of View wants to shed light on the known and potential chemistry of DNA and RNA methylation and demethylation. Understanding the chemistry of these processes on a molecular level is the first step towards a deeper knowledge about their regulation and function and will help us to find ways how nucleobase methylation can be manipulated to treat diseases.
Topics: Animals; DNA; DNA Methylation; Demethylation; Epigenesis, Genetic; Humans; Methylation; RNA
PubMed: 28440690
DOI: 10.1080/15476286.2017.1318241