Association of DNA methyltransferases expression with global and gene‐specific DNA methylation in colorectal cancer cells

Sarabi, Mostafa Moradi; Naghibalhossaini, Fakhraddin

doi:10.1002/cbf.3126

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…As shown in Supplemental Figure S5A , EZH2 was overexpressed in Stage III–IV CRCs (1.55-fold increase, p=0.03), but not in ACF ( Supplemental Figure S5B ). We also interrogated the RNA-Seq dataset for the expression levels of the DNA methyltransferases (DNMTs), a group of genes ( DNMT1, DNMT3A and DNMT3B ) that are often up-regulated in CRC 34 . As shown in Supplemental Figure S5A&B , DNMT1 and DNMT3B are overexpressed in cancer samples, but not in ACF.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia

Hanley

Hahn

et al. 2017

Oncogene

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Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study we have combined laser-capture microdissection (LCM) with reduced representation bisulfite sequencing (RRBS) to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology (GO) analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2 (PRC2). Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. While aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Together, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

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Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia

Hanley

Hahn

et al. 2017

Oncogene

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“…In general, DNMTs determine the DNA methylation pattern of the genome. Alterations in the expression or epigenetic regulation of DNMTs will elicit methylation changes at both regional and global genomic levels (21,22). On the other hand, besides the classic interaction of ligand-bound ER dimers with estrogen-responsive elements in target gene promoters, estrogen also regulates gene expression via multiple nonclassic pathways.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

Yang

Sun

Kandhi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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To elucidate molecular mechanisms responsible for the sexually dimorphic phenotype of soluble epoxide hydrolase (sEH) expression, we tested the hypothesis that female-specific down-regulation of sEH expression is driven by estrogen-dependent methylation of the gene. Mesenteric arteries isolated from male, female, ovariectomized female (OV), and OV with estrogen replacement (OVE) mice, as well as the human cell line (HEK293T) were used. Methylation-specific PCR and bisulfite genomic sequencing analysis indicate significant increases in DNA/CG methylation in vessels of female and OVE compared with those of male and OV mice. The same increase in CG methylation was also observed in male vessels incubated with a physiological concentration of 17β-estradiol (17β-E) for 48 hours. All vessels that displayed increases in CG methylation were concomitantly associated with decreases in their mRNA and protein, suggesting a methylation-induced gene silencing. Transient transfection assays indicate that the activity of promoter-coding luciferase was significantly attenuated in HEK293T cells treated with 17β-E, which was prevented by additional treatment with an estrogen receptor antagonist (ICI). ChIP analysis indicates significantly reduced binding activities of transcription factors (including SP1, AP-1, and NF-κB with their binding elements located in the promoter) in vessels of female mice and human cells treated with 17β-E, responses that were prevented by ICI and Decitabine (DNA methyltransferase inhibitor), respectively. In conclusion, estrogen/estrogen receptor-dependent methylation of the promoter of gene silences sEH expression, which is involved in specific transcription factor-directed regulatory pathways.

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“…All of the measurements were performed in triplicate within each experiment. For more information please refer to our previously published article [2].…”

Section: Analysis Of Global Dna Methylationmentioning

confidence: 99%

“…DNA methylation is described as an epigenetic mechanism involving the transfer of methyl group at the 5′ carbon of cytosine nucleotides to form 5-methyl cytosine (5-mC) in CpG islands and modulates gene expression [1][2][3]. It has been suggested that three active forms of DNA methyltransferases (DNMT) including DNMT1, DNMT3A and DNMT3B are responsible for maintenance and generation of DNA methylation [4].…”

Section: Introductionmentioning

confidence: 99%

Nicotine attenuates global genomic DNA methylation by influencing DNMTs gene expression in human endometrial stromal cells

et al. 2020

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Background: There is increasing evidence indicating an incidence of infertility and also the risk of endometrial cancers among smokers. However, the mechanism underlying nicotine adverse effect on female reproduction remains unclear. Growing evidence has suggested that environmental exposures such as nicotine could modulate the epigenome. No study has yet been published to evaluate the direct effect of nicotine on the epigenome profiling of human endometrial stromal cells (HESC). Herein, we decided to examine the direct effects of nicotine on global genomic DNA methylation status and DNA methyl-transferases (DNMTs) gene expression in HESC. HESC were treated with different doses of nicotine (0 or control, 10 − 11 , 10 − 8 and 10 − 6) M for 24 h and their genomic global DNA methylation and gene expression of DNMTs (DNMT1, DNMT3A, and DNMT3B) were investigated using ELISA and real-time PCR, respectively. Results: Nicotine treatments reduced the average level of DNMTs gene expression by 90, 79, and 73.4% in 10 − 11 , 10 − 8 and 10 − 6 M of nicotine treated cells as compared to control cells, respectively (p < 0.05). Also, 10 − 8 and 10 − 6 M of nicotine concentrations effectively reduced the amounts of 5-methylated cytosine (5-mC) by 1.09 and 1.87% compared to control cells, respectively (p < 0.05). The 5-mC percentages were positively correlated with the relative cellular DNMTs expression in HESC as verified by the Pearson correlation test. Conclusion: An interesting possibility raised by the current study is that the reduced genomic global DNA methylation level in HESC may be partly due to the suppression of DNMTs gene expression caused by nicotine in these cells.

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Association of DNA methyltransferases expression with global and gene‐specific DNA methylation in colorectal cancer cells

Cited by 42 publications

References 39 publications

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia

Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

Nicotine attenuates global genomic DNA methylation by influencing DNMTs gene expression in human endometrial stromal cells

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