Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The process of p15 CpG island methylation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated, using MO7e cells. The cells proliferating in response to GM-CSF+fetal bovine serum (FBS) were almost fully methylated in the p15 CpG island. The withdrawal of both GM-CSF and FBS for 48 h reduced the cell viability, and increased the frequency of alleles with completely or partially demethylated CpG sites by approximately 50%. Viable cells were responsible for this epigenetic change. The add-back of GM-CSF restored the methylation. Seventy-two hours withdrawal of GM-CSF+FBS followed by 24-h exposure to inhibitors for DNA methyltransferase (DNMT) and histone deacetylase (HDAC) caused the demethylation of nearly all CpG sites in the p15 CpG island on every allele sequenced. When GM-CSF was re-added after 96-h treatment, the cells exhibited p15 transcriptional silencing via the methylation. The initial methylation event encompassed the entire CpG island. No new methylated alleles appeared in the coexistence of the DNMT and HDAC inhibitors. Taken together, GM-CSF may be able to induce de novo methylation of the p15 gene, using HDAC(s) as well as DNMT(s).
Cytokine 2005 Aug 07
PMID:Granulocyte-macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopoietic cells. 1599 79

Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G(0) to G(1) phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease.
 ...
PMID:Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. 1988 73

The human IL-15RA gene encoding the alpha chain of the IL-15 receptor is expressed in a variety of immune and non-immune cell types from different tissues, and generates multiple splicing events of functional importance. We aimed to evaluate expression of IL-15RA transcripts generated by alternative usage of transcription start site (Var1 and Var2) and by deletion of exon 3 (Del3), exon 2 (Del2), or both (Del2,3) in different human tissues. Since a CpG island was found near to the IL-15RA gene transcription start site, we also investigated the role of DNA methylation on the expression of IL-15RA full-length and alternative transcripts fragments in peripheral blood mononuclear cells (PBMC). IL-15RA transcription of functional (full-length and del 3) and non-functional (del 2 and del 2,3) variants was detected in many tissues, however, the number of different IL-15RA transcripts variants detected in each tissue did not correlate with the level of gene expression. IL-15RA transcript variants Var1 and Var2 presented similar expression levels in different human tissues. However, we found a distinct expression profile of functional and non-functional IL-15RA transcripts fragments. A preferential expression of transcripts that bind IL-15 compared to IL-15 non-binding transcripts was seen in the tissues investigated. When PBMC cultures were treated with 5-azacitidine (AZA), a DNA methyltransferase inhibitor, we detected a significant increase in IL-15RA copy number. Only alternative exon skipping events of Var1 (Del 2, Del 3 and Del 2, 3) were altered by AZA treatment, which is consistent with the CpG island localization in the regulatory region 5' upstream of the transcription start site of Var1 and not of Var2. Therefore, this work shows a broad expression pattern of functional IL-15RA splicing forms and suggests a regulatory role of DNA methylation in IL-15RA transcript Var1 expression in mononuclear cells.
Eur Cytokine Netw 2010 Dec
PMID:Tissue-specific expression of IL-15RA alternative splicing transcripts and its regulation by DNA methylation. 2109 93