Hypoxia induces rapid changes to histone methylation reprogramming chromatin for the cellular response

Molecular dioxygenases include JmjC-containing histone demethylases and PHD enzymes, but only PHDs are considered to be molecular oxygen sensors in cells. Although, it is known that hypoxia can alter chromatin, whether this is a direct effect on histone demethylases or due to hypoxia induced HIF-dependent transcriptional changes is not known. Here, we report that hypoxia induces a rapid and HIF-independent alteration to a variety of histone methylation marks. Genomic locations of H3K4me3 and H3K36me3 following short hypoxia predict the hypoxia gene signature observed several hours later in cells. We show that KDM5A inactivation mimics hypoxic changes to H3K4me3 in its targets and is required for the cellular response to hypoxia. Our results demonstrate a direct link between oxygen sensing and chromatin changes via KDM inhibition.