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)

Phosphorylation is critically involved in synaptic plasticity and memory. Recent studies have shown that another posttranslational modification, acetylation, particularly of histone H3, also plays important roles in long-term potentiation and memory. However, activity-dependent modification of different histones of the nucleosome is not clearly understood. Here we show that depolarization enhances acetylation of histone H2B in the CA1 region of the hippocampus. Depolarization-induced H2B acetylation is dependent on calcium/calmodulin-dependent kinase and extracellular signal-regulated kinase activity. In addition, inhibition of DNA methyltransferase activity also abolishes depolarization-induced increase in H2B acetylation. These results show that acetylation of histone H2B is regulated in an activity-dependent manner by the molecular events important for synaptic plasticity and memory.
 ...
PMID:Depolarization induces acetylation of histone H2B in the hippocampus. 2016 51

Neurospora crassa utilizes DNA methylation to inhibit transcription of heterochromatin. DNA methylation is controlled by the histone methyltransferase DIM-5, which trimethylates histone H3 lysine 9, leading to recruitment of the DNA methyltransferase DIM-2. Previous work demonstrated that the histone deacetylase (HDAC) inhibitor trichostatin A caused a reduction in DNA methylation, suggesting involvement of histone deacetylation in DNA methylation. We therefore created mutants of each of the four classical N. crassa HDAC genes and tested their effect on histone acetylation levels and DNA methylation. Global increases in H3 and H4 acetylation levels were observed in both the hda-3 and the hda-4 mutants. Mutation of two of the genes, hda-1 and hda-3, caused partial loss of DNA methylation. The site-specific loss of DNA methylation in hda-1 correlated with loss of H3 lysine 9 trimethylation and increased H3 acetylation. In addition, an increase in H2B acetylation was observed by two-dimensional gel electrophoresis of histones of the hda-1 mutant. We found a similar increase in the Schizosaccharomyces pombe Clr3 mutant, suggesting that this HDAC has a previously unrecognized substrate and raising the possibility that the acetylation state of H2B may play a role in the regulation of DNA methylation and heterochromatin formation.
 ...
PMID:H2B- and H3-specific histone deacetylases are required for DNA methylation in Neurospora crassa. 2087 59

Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases.
 ...
PMID:Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease. 2096 78

DNA methylation is an important epigenetic mark that is known to induce chromatin condensation and gene silencing. We used a time-domain fluorescence lifetime measurement to quantify the effects of DNA hypermethylation on the conformation and dynamics of a nucleosome. Nucleosomes reconstituted on an unmethylated and a methylated DNA both exhibit dynamic conformations under physiological conditions. The DNA end breathing motion and the H2A-H2B dimer destabilization dominate the dynamic behavior of nucleosomes at low to medium ionic strength. Extensive DNA CpG methylation, surprisingly, does not help to restrain the DNA breathing motion, but facilitates the formation of a more open nucleosome conformation. The presence of the divalent cation, Mg(2+), essential for chromatin compaction, and the methyl donor molecule SAM, required for DNA methyltransferase reaction, facilitate the compaction of both types of nucleosomes. The difference between the unmethylated and the methylated nucleosome persists within a broad range of salt concentrations, but vanishes under high magnesium concentrations. Reduced DNA backbone rigidity due to the presence of methyl groups is believed to contribute to the observed structural and dynamic differences. The observation of this study suggests that DNA methylation alone does not compact chromatin at the nucleosomal level and provides molecular details to understand the regulatory role of DNA methylation in gene expression.
 ...
PMID:The effect of DNA CpG methylation on the dynamic conformation of a nucleosome. 2326 52

Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 - 4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.
...
PMID:Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy. 2596 89