Hypoxic inhibition of JMJD3 reduces H3K27me3 demethylation and induction of the STAT6 target gene CCL18.

Hypoxia, by activating transcription factors induces transcription of some genes but it also reduces mRNA synthesis by mechanisms that are poorly defined. Activation of human macrophages with interleukin (IL)-4 showed that up-regulation of some IL-4 target genes was reduced when macrophages were incubated at 1% oxygen. Hypoxia impaired induction of chemokine (C-C motif) ligand 18 (CCL18), although IL-4-induced DNA binding of the transcription factor STAT6 remained intact. In contrast, induction of serine peptidase inhibitor, Kunitz type (SPINT)2, another IL-4/STAT6 target gene, was not affected by hypoxia. The repressive histone mark histone 3 lysine 27 trimethylation (H3K27me3), known to prevent chromatin remodelling and transcription, was removed from the SPINT2 but not the CCL18 gene locus under hypoxia or dimethyloxalylglycine-treatment. The H3K27me3 demethylase JMJD3 was required for CCL18 gene induction but dispensable for induction of SPINT2. Our data indicate that hypoxic inhibition of JMJD3 activity reduces demethylation of H3K27me3, nucleosome removal, and hence induction of the STAT6 target gene CCL18, while induction of other STAT6-inducible genes such as SPINT2 remained unaffected by JMJD3. In contrast to mouse MΦ in human cells JMJD3 is not recruited by transcription factors like IRF4, KL4, or PPARγ to convey specificity in gene induction.