Hypoxic Stress Induces Dimethylated Histone H3 Lysine 9 through Histone Methyltransferase G9a in Mammalian Cells

Abstract

Dimethylated histone H3 lysine 9 (H3K9me2) is a critical epigenetic mark for gene repression and silencing and plays an essential role in embryogenesis and carcinogenesis. Here, we investigated the effects of hypoxic stress on H3K9me2 at both global and gene-specific level. We found that hypoxia increased global H3K9me2 in several mammalian cell lines. This hypoxia-induced H3K9me2 was temporally correlated with an increase in histone methyltransferase G9a protein and enzyme activity. The increase in H3K9me2 was significantly mitigated in G9a À/À mouse embryonic stem cells following hypoxia challenge, indicating that G9a was involved in the hypoxia-induced H3K9me2. In addition to the activation of G9a, our results also indicated that hypoxia increased H3K9me2 by inhibiting H3K9 demethylation processes. Hypoxic mimetics, such as deferoxamine and dimethyloxalylglycine, were also found to increase H3K9me2 as well as G9a protein and activity. Finally, hypoxia increased H3K9me2 in the promoter regions of the Mlh1 and Dhfr genes, and these increases temporally correlated with the repression of these genes. Collectively, these results indicate that G9a plays an important role in the hypoxia-induced H3K9me2, which would inhibit the expression of several genes that would likely lead to solid tumor progression. (Cancer Res 2006; 66(18): 9009-16)

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Thus, a global decrease in H3K9 acetylation is a possible consequence of hypoxia-induced HDAC upregulation (Johnson et al, 2008). In fact, the H3K9 acetylation reduction occurs by the increase G9a histone methyltransferase expression, which raises global H3K9 methylation, a repressive histone mark (Chen et al, 2006).…”

Epigenetics: The epicenter of the hypoxic response

“…25,28 One potential mechanism of increased H3K9me2 is believed to be mediated by the histone methyltransferase G9a, which has also been shown to increase in hypoxia. 28 In addition to the emerging role of DNA methylation in regulating HIF binding to target genes, it has been shown that hypoxia can itself promote epigenetic changes in cancer cell lines. Using HPLC to quantify the global levels of 5'-methylcytidine in human colorectal and melanoma cell lines, Shahrzad et al demonstrated that exposure to anoxia (≤0.1% oxygen, 24 hours) induces a 15-20% reduction in CpG methylation.…”

Ischemia dysregulates DNA methyltransferases andp16INK4amethylation in human colorectal cancer cells

“…Costa and colleagues showed that hypoxia increased H3K9me2, as well as the histone methyltransferase G9a protein and enzyme activity in human lung carcinoma cells. 39 Promoter regions of Mlh1 and Dhfr genes had increased H3K9me2 and decreased expression as a result of the hypoxia. 39 A recent study has shown that hypoxia decreased histone H3 acetylation at the Mlh1 promoter in mouse colon cells and resulted in reduced MLH1 expression at mRNA and protein levels.…”

“…39 Promoter regions of Mlh1 and Dhfr genes had increased H3K9me2 and decreased expression as a result of the hypoxia. 39 A recent study has shown that hypoxia decreased histone H3 acetylation at the Mlh1 promoter in mouse colon cells and resulted in reduced MLH1 expression at mRNA and protein levels. 40 Solid tumors undergo angiogenesis to meet the increased demand for oxygen and nutrients.…”