Novel Epigenetic Controlling of Hypoxia Pathway Related to Overexpression and Promoter Hypomethylation of TET1 and TET2 in RPE Cells

Abstract

CpG methylation of DNA takes part in a specific epigenetic memory that plays crucial roles in the differentiation and abnormality of the cells. The methylation pattern aberration of genomes is affected in three ways, namely DNA methyltransferase (DNMT), ten-eleven translocation (TET), and methyl-binding domain (MBD) proteins. Of these, TET enzymes have recently been demonstrated to be master modifier enzymes in the DNA methylation process. Additionally, recent studies emphasize that not only epigenetic phenomena play a role in controlling hypoxia pathway, but the hypoxia condition also triggers hypomethylation of genomes that may help with the expression of hypoxia pathway genes. In this study, we suggested that TET1 and TET2 could play a role in the demethylation of genomes under chemical hypoxia conditions. Herein, the evaluating methylation status and mRNA expression of mentioned genes were utilized through real-time PCR and methylation-specific PCR (MSP), respectively. Our results showed that TET1 and TET2 genes were overexpressed (P < 0.05) under chemical hypoxia conditions in Retinal Pigment Epithelial (RPE) cells, whereas the promoter methylation status of them were hypomethylated in the same condition. Therefore, chemical hypoxia not only causes overexpression of TET1 and TET2 but also could gradually do promoter demethylation of same genes. This is the first study to show the relationship between epigenetics and the expression of mentioned genes related to hypoxia pathways. Furthermore, it seems that these associations in RPE cells are subjected to chemical hypoxia as a mechanism that could play a crucial role in methylation pattern changes of hypoxia-related diseases such as cancer and ischemia. J. Cell. Biochem. 118: 3193-3204, 2017. © 2017 Wiley Periodicals, Inc.

Dynamic regulation of epigenetic demethylation by oxygen availability and cellular redox

“…Intriguingly, several studies have suggested that the transcriptional expression of the TETs themselves may further be regulated by hypoxia-induced changes in 5hmC (and thus potentially 5mC). Thus, the methylation status of both the Tet1 and Tet2 gene promoters in retinal pigment epithelial cells were found to become hypomethylated under conditions of chemically-induced hypoxia [90]. In addition, as stated above, we observed a transitory burst of 5hmC generation during early-differentiating ESCs that was dependent upon TET1 and was inhibited under low (1%) O 2 [44].…”

“…In addition to the ability of [O 2 ] to regulate TET activity, multiple studies have demonstrated the transcriptional expression of TET enzymes to be dependent upon the cellular O 2 availability. Thus, increases in TET1/2 and 3 have all been reported in various cell types under hypoxic conditions [71,[90][91][92][93][94] which, in some cases, have been demonstrated to be dependent upon HIF1 [71,91,93]. As in the case of TET activity, the levels of expression of the different TET proteins show distinct patterns of sensitivity to different levels of hypoxia [93].…”

Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial–mesenchymal transition in cancer cells

“…Furthermore, MMP8 facilitates SIRT1‐Zeb1 interaction through association with Zeb1 (Sun et al, ). Also, according to studies, a transcriptional repressor complex including SIRT1, Twist1, and methyl‐CpG binding domain (MBD) protein‐1, can suppress the expression of E‐cadherin (Alivand, Soheili, Pornour, Solali, & Sabouni, ; Xu, Zhu, et al, ) (Figure ).…”

Aberrant miRNA promoter methylation and EMT‐involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications

“…DNA methylation and miRNA are important epigenetic markers that affect gene expression in cancerous cells (Loginov et al, ). Epigenetic phenomena controls both mRNA and miRNA expression of cancers; therefore, epigenetic events and miRNA could play mutual roles in BC (Alivand, Soheili, Pornour, & Sabouni, ; Loginov et al, ). The expression of miRNA plays a crucial role in the progression and metastasis of BC and can be distinguished in ductal to lobular morphologies, tumor subclones, and the stages and grades of BC (Loginov et al, ; Raychaudhuri et al, ).…”