Abstract
BackgroundTrimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity during development and differentiation. Whether H3K4me3 and H3K27me3 changes dynamically in response to altered microenvironmental conditions, including low-oxygen conditions commonly present in solid tumors, is relatively unknown. Demethylation of H3K4me3 and H3K27me3 is mediated by oxygen and 2-oxoglutarate dioxygenases enzymes, suggesting that oxygen deprivation (hypoxia) may influence histone trimethylation. Using the MCF7 breast epithelial adenocarcinoma cell model, we have determined the relationship between epigenomic and transcriptomic reprogramming as a function of fluctuating oxygen tension.ResultsWe find that in MCF7, H3K4me3 and H3K27me3 marks rapidly increase at specific locations throughout the genome and are largely reversed upon reoxygenation. Whereas dynamic changes are relatively highest for H3K27me3 marking under hypoxic conditions, H3K4me3 occupation is identified as the defining epigenetic marker of transcriptional control. In agreement with the global increase of H3K27 trimethylation, we provide direct evidence that the histone H3K27me3 demethylase KDM6B/JMJD3 is inactivated by limited oxygen. In situ immunohistochemical analysis confirms a marked rise of histone trimethylation in hypoxic tumor areas. Acquisition of H3K27me3 at H3K4me3-marked loci results in a striking increase in “bivalent” epigenetic marking. Hypoxia-induced bivalency substantially overlaps with embryonal stem cell-associated genic bivalency and is retained at numerous loci upon reoxygenation. Transcriptional activity is selectively and progressively dampened at bivalently marked loci upon repeated exposure to hypoxia, indicating that this subset of genes uniquely maintains the potential for epigenetic regulation by KDM activity.ConclusionsThese data suggest that dynamic regulation of the epigenetic state within the tumor environment may have important consequences for tumor plasticity and biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0086-0) contains supplementary material, which is available to authorized users.
Highlights
Trimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity dur‐ ing development and differentiation
We report that the histone H3K27me3 demethylase KDM6B/JMJD3 is inactivated by limited oxygen and show a consequential rapid increase of genomic histone 3 lysine trimethylated (H3K4me3) and H3K27me3 markings in vitro and in vivo
Increased hypoxia‐induced histone H3 methylation in vivo and in vitro Based on their structural relatedness to 2-OG-dependent dioxygenases, we hypothesized that the catalytic activity of histone H3K27me3 and H3K4me3 demethylases would be inhibited under hypoxic conditions [18, 20]
Summary
Trimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity dur‐ ing development and differentiation. Demethylation of H3K4me and H3K27me is mediated by oxygen and 2-oxoglutarate dioxygenases enzymes, suggesting that oxygen deprivation (hypoxia) may influence histone trimethylation. Cancer cells in solid tumors are often exposed to repeated cycles of oxygen deprivation and reoxygenation that result from inadequate blood supply due to poorly developed vasculature [1]. Tumor oxygenation in situ is known to reach very low values, and repeated oxygen deprivation and reoxygenation promote tumor stem cell properties, metastasis, and negatively affect patient prognosis as adaptive responses to hypoxia severely decrease efficacy of both ionizing radiation and chemotherapy [2,3,4,5,6,7]. Transcriptional changes in hypoxic cancer cells are controlled by several well-understood hypoxia response pathways [12,13,14]. PHDs belong to a larger family of 2-oxoglutarate-dependent dioxygenases (2-OGDO), including histone demethylases, whose activity is controlled by oxygen, iron and 2-oxoglutarate (2-OG; α-ketoglutarate) [18,19,20]
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