scholarly journals Design and synthesis of water-soluble grifolin prodrugs for DNA methyltransferase 1 (DNMT1) down-regulation

RSC Advances ◽  
2021 ◽  
Vol 11 (61) ◽  
pp. 38907-38914
Author(s):  
Liguo Wang ◽  
Yue Wu ◽  
Zhenzhen Li ◽  
Tianlong Lan ◽  
Xu Zhao ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Water Soluble ◽  
Tumor Proliferation ◽  
Dna Methyltransferase 1 ◽  
Down Regulation ◽  
Design And Synthesis ◽  
Methyltransferase 1

In this work, a series of prodrugs of grifolin with much improved solubility and stability were designed and synthesis, which potently downregulated DNMT1 and inhibited tumor proliferation in vitro and in vivo.

scholarly journals Silencing DNA methyltransferase 1 leads to the activation of the esophageal suppressor gene p16 in vitro and in vivo

2017 ◽  
Vol 14 (3) ◽  
pp. 3077-3081 ◽  
Author(s):  
Jian Bai ◽  
Xue Zhang ◽  
Bangqing Liu ◽  
Haiyong Wang ◽  
Zhenzong Du ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Suppressor Gene ◽  
Dna Methyltransferase 1 ◽  
Methyltransferase 1

Inhibition of DNA methyltransferase-1 instigates the expression of DNA methyltransferase-3a in angioplasty-induced restenosis

2018 ◽  
Vol 96 (10) ◽  
pp. 1030-1039 ◽  
Author(s):  
Chandra S. Boosani ◽  
Palanikumar Gunasekar ◽  
Megan Block ◽  
Wanlin Jiang ◽  
Zefu Zhang ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Cytokine Signaling ◽  
Dna Methyltransferase 1 ◽  
Compensatory Mechanisms ◽  
Dna Methyltransferase 3A ◽  
Methyltransferase 1

Increased expression of DNA methyltransferase-1 (DNMT1) associates with the progression of many human diseases. Because DNMT1 induces cell proliferation, drugs that inhibit DNMT1 have been used to treat proliferative diseases. Because these drugs are nonspecific inhibitors of DNMT1, subsidiary events or the compensatory mechanisms that are activated in the absence of DNMT1 limit their therapeutic application. Here, we studied the molecular mechanisms that occur during angioplasty-induced restenosis and found that DNMT1 inhibition in both in vitro and in vivo approaches resulted in the induction of DNA methyltransferase-3a (DNMT3a) expression. In vascular smooth muscle cells (VSMCs), the microRNA hsa-miR-1264 mimic, specifically inhibiting DNMT1, induced nuclear expression of DNMT3a. On the contrary, there was no induced expression of DNMT3a in VSMCs that were transfected with hsa-miR-1264 inhibitor. Further, ectopic expression of suppressor of cytokine signaling 3 (SOCS3) through adeno-associated virus (AAV)-mediated gene delivery in the coronary arteries of Yucatan microswine showed inhibition of both DNMT1 and DNMT3a in vivo. These findings show the existence of an inter-regulatory mechanism between DNMT1 and DNMT3a where, in the absence of DNMT1, induction of DNMT3a compensates for the loss of DNMT1 functions, suggesting that the inhibition of both DNMT1 and DNMT3a are required to prevent restenosis.

SUMOylation enhances DNA methyltransferase 1 activity

2009 ◽  
Vol 421 (3) ◽  
pp. 449-461 ◽  
Author(s):  
Bongyong Lee ◽  
Mark T. Muller
Keyword(s):  
Dna Methyltransferase ◽  
Gene Control ◽  
Dna Methyltransferase 1 ◽  
Dna Interactions ◽  
Protein Dna Interactions ◽  
Catalytically Active ◽  
Endogenous Activity ◽  
Methyltransferase 1

DNA methylation regulates gene expression through a complex network of protein–protein and protein–DNA interactions in chromatin. The maintenance methylase, DNMT1 (DNA methyltransferase 1), is a prominent enzyme in the process that is linked to DNA replication and drives the heritable nature of epigenetic modifications. The mechanistic details that explain how DNMT1 catalytic action is directed and regulated in chromatin are important in our overall understanding of gene control. In this work, we show that DNMT1 is modified by SUMOylation and we have mapped these SUMOylation sites by defined mutations. SUMOylated DNMT1 is catalytically active on genomic DNA in vivo and we find that SUMOylation significantly enhances the methylase activity of DNMT1 both in vitro and in chromatin. These data suggest that SUMOylation modulates the endogenous activity of a prominent epigenetic maintenance pathway in somatic cells.

3 IN VITRO MATURATION ALTERS GENE EXPRESSION IN MOUSE OOCYTES

2008 ◽  
Vol 20 (1) ◽  
pp. 82
Author(s):  
M. Paczkowski ◽  
C. Bidwell ◽  
D. Spurlock ◽  
J. Waddell ◽  
R. L. Krisher
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Dna Methyltransferase ◽  
In Vitro Maturation ◽  
Fold Increase ◽  
Developmental Competence ◽  
Differentially Expressed ◽  
Dna Methyltransferase 1

The in vitro culture environment significantly impacts nuclear maturation, fertilization, embryonic development, and epigenetic competence; however, our knowledge of the effects of in vitro maturation on oocyte developmental competence, and specifically cytoplasmic maturation, is limited. The objective of this experiment was to identify alterations in the transcriptome of oocytes matured in vitro compared to those matured in vivo that correlate to developmental competence. Immature oocytes were collected from Day 26 and 7-8-week-old B6D2F1 mice 48 h post-pregnant mare serum gonadotropin (PMSG) administration and matured for 16 h in Gmat supplemented with 0.5 mm citric acid, 0.5 mm cysteamine, 100 ng mL–1 epidermal growth factor (EGF), 0.05% insulin-transferrin-selenium (ITS; v/v), 0.01% recombumin (v/v) and 2 mg mL–1 fetuin. In vivo-matured oocytes from females of the same ages were collected from the oviducts 62 h post-PMSG and 14 h post-hCG and mating to vasectomized males. In vivo- and in vitro-matured oocytes were identified visually by the presence of the first polar body. Mature oocytes were pooled into three groups of 150 oocytes per treatment and lysed; poly A+ RNA was extracted. Samples were processed through two cycles of linear amplification and hybridized to the GeneChip� Mouse Genome 430 2.0 Array (Affymetrix, Inc., Santa Clara, CA, USA), with three arrays per treatment. Microarray data were sorted and filtered to include genes that were classified as having two present calls per treatment. The data were then normalized to the chip median and analyzed using a one-way analysis of variance; the level of significance was calculated at P < 0.01. In total, 2.17% (482/22170) and 1.61% (358/22170) of genes were differentially expressed between in vitro- and in vivo-matured oocytes in Day 26 and 7–8-week-old mice, respectively. However, 72.82% (351/482) and 67.87% (243/358) of differentially expressed genes had increased abundance in the in vitro- and in vivo-matured oocytes, respectively. Transcripts involved in gene expression, cellular growth and proliferation, and cellular development were increased in in vivo-matured oocytes from both age groups compared to those matured in vitro. Cell death was one of the higher ranking functional groups increased in the 7–8-week-old in vitro-matured oocytes compared to the 7–8-week-old in vivo-matured oocytes. Specific genes altered by in vitro maturation conditions in Day 26 oocytes were DNA methyltransferase 1 (>7-fold increase in vivo), caspase 8 (>4-fold increase in vivo), and eukaryotic translation initiation factor 1B (>4-fold increase in vivo). DNA methyltransferase 1 and ubiquitin-conjugating enzyme E2T were significantly increased in in vivo-matured 7–8-week-old oocytes (>3-fold and >5-fold, respectively). These results indicate that gene expression is altered in oocytes matured in vitro compared to those matured in vivo. Based on the functional annotations of genes differentially expressed, dysregulation of gene expression in the oocyte resulting in altered DNA methylation and an up-regulation in cell death pathways are potential developmental mechanisms influenced by in vitro culture conditions that correlate to reduced embryonic developmental potential.

Modulation of DNA Methyltransferase 1 Profile by γ-lrradiation Followed by Methyl Donor Starvation

Pteridines ◽  
2005 ◽  
Vol 16 (4) ◽  
pp. 159-165 ◽  
Author(s):  
Vipen Batra ◽  
Vellappan Kesavan ◽  
Kaushala P. Mishra
Keyword(s):  
Dna Methylation ◽  
Ionizing Radiation ◽  
Dna Methyltransferase ◽  
Water Soluble ◽  
Dna Methyltransferase 1 ◽  
Radiation Stress ◽  
Methyl Donors ◽  
Methyl Donor ◽  
Carbon Transfer ◽  
Methyltransferase 1

Abstract Role of one-carbon transfer agents methyl donors namely folate, choline and methionine in DNA methylation has been the subject of extensive investigation. The methylation pattern of DNA is established during embryogenesis and is subsequently maintained by maintenance methylation activity of the enzyme DNA methyltransferase 1 (dnmt 1). Ionizing radiation is known to extensively damage the DNA. Folate, a water-soluble vitamin, is known to contribute towards repair of damaged DNA due to its role in synthesis of nucleotide base adenine, guanine and thymidylate. Sufficient dietary availability of methyl donors, therefore, might have ability to modify radiation effects. In the present study, modifications in levels of dnmt 1 by g-irradiation followed by methyl donor starvation were observed. Experiments showed a dose and methyl donors starvation dependent attenuation in dnmt 1 activity. Attenuation of dnmt 1 activity was most significant for diet deprived of all the three methyl donors. Ionizing radiation and methyl donor deficiency were observed to act synergistically towards inhibiting dnmt 1 activity. Present results suggested possibility of interaction among folate, methionine and choline deficiency to potentate symptoms of ionizing radiation stress. These enzymatic modifications might contribute to altered DNA methylation after chronic feeding of methyl donor free diets after gamma irradiation. These results suggest that dietary availability of methyl donors and γ-radiation stress might significantly alter the dnmt 1 profile.

scholarly journals BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo

2018 ◽  
Vol 293 (50) ◽  
pp. 19466-19475 ◽  
Author(s):  
Olya Yarychkivska ◽  
Zoha Shahabuddin ◽  
Nicole Comfort ◽  
Mathieu Boulard ◽  
Timothy H. Bestor
Keyword(s):  
Dna Methyltransferase ◽  
De Novo ◽  
Dna Methyltransferase 1 ◽  
Maintenance Methylation ◽  
Methyltransferase 1

scholarly journals EPHA3 Contributes to Epigenetic Suppression of PTEN in Radioresistant Head and Neck Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 599
Author(s):  
Song-Hee Kim ◽  
Byung-Chul Kang ◽  
Daseul Seong ◽  
Won-Hyeok Lee ◽  
Jae-Hee An ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cancer Cells ◽  
Neck Cancer ◽  
Dna Methyltransferase ◽  
Regulatory Mechanism ◽  
Dna Methyltransferase 1 ◽  
Epigenetic Suppression

EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.

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