Hypoxia Induces Trimethylated H3 Lysine 4 by Inhibition of JARID1A Demethylase

Abstract

Histone H3 lysine 4 (H3K4) trimethylation (H3K4me3) at the promoter region of genes has been linked to transcriptional activation. In the present study, we found that hypoxia (1% oxygen) increased H3K4me3 in both normal human bronchial epithelial Beas-2B cells and human lung carcinoma A549 cells. The increase of H3K4me3 from hypoxia was likely caused by the inhibition of H3K4 demethylating activity, as hypoxia still increased H3K4me3 in methionine-deficient medium. Furthermore, an in vitro histone demethylation assay showed that 1% oxygen decreased the activity of H3K4 demethylases in Beas-2B nuclear extracts because ambient oxygen tensions were required for the demethylation reaction to proceed. Hypoxia only minimally increased H3K4me3 in the BEAS-2B cells with knockdown of JARID1A, which is the major histone H3K4 demethylase in this cell line. However, the mRNA and protein levels of JARID1A were not affected by hypoxia. GeneChip and pathway analysis in JARID1A knockdown Beas-2B cells revealed that JARID1A regulates the expression of hundreds of genes involved in different cellular functions, including tumorigenesis. Knocking down of JARID1A increased H3K4me3 at the promoters of HMOX1 and DAF genes. Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and genespecific levels, leading to the altered programs of gene expression and tumor progression.

Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases

“…S-Adenosylmethionine, which is synthesized from methionine and ATP, is the sole methyl donor for methyltransferase reactions. Histone methylation changes detected in cells grown in media depleted of methionine will predominantly reflect alterations in demethylation as opposed to methylation (33,34,36,37). Fig.…”

“…Previously, it has been shown that the JMJC domain-containing histone demethylase KDM3A is highly sensitive to inhibition by carcinogenic nickel ions (28,30,31). Others have demonstrated that various dioxygenase inhibitors such as ␣-KG analogs, hypoxia, ⅐ NO, reactive oxygen species, CoCl 2 , and iron chelators like desferrioxamine (DFO) all increase histone methylation, most probably by reducing demethylase activity (32)(33)(34)(35)(36)(37).…”

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

“…In contrast, hypoxia increases global levels of H3K4me3 in alveolar A549 and bronchial Beas-2B cell lines, due to the inhibition of demethylation process, particularly, demethylase (Lysinespecific demethylase 5A). Therefore, hypoxia targets lysinespecific demethylase 5A, which induces H3K4me3 both globally and at gene-specific promoters (heme oxygenase-1 and decay-accelerating factor), thus promoting alterations in the pattern of gene expression and tumor progression (194). Understanding the molecular epigenetic mechanism that involves HDMs in COPD/lung cancer will influence treatment options and outcomes in COPD, lung cancer, and other chronic lung diseases associated with tobacco smoking (139).…”

Application of Divergence Entropy to Characterize the Structure of the Hydrophobic Core in DNA Interacting Proteins

“…Domains selected for analysis include fragments responsible for DNA interactions; specifically, the β-hairpin which, in the case of PHD domains, is characterized by the stabilizing presence of zinc (Zn 2+ ) ions. Our selection is motivated by the fact that these domains participate in epigenetic phenomena (histone demethylase activity) [18] as well as in polycomb complexation [19][20][21], both of which are important in the context of pathological (disease-related) processes [22,23].…”