Jmjd3 contributes to the control of gene expression in LPS-activated macrophages

Abstract

Jmjd3, a JmjC family histone demethylase, is induced by the transcription factor NF-kB in response to microbial stimuli. Jmjd3 erases H3K27me3, a histone mark associated with transcriptional repression and involved in lineage determination. However, the specific contribution of Jmjd3 induction and H3K27me3 demethylation to inflammatory gene expression remains unknown. Using chromatin immunoprecipitation-sequencing we found that Jmjd3 is preferentially recruited to transcription start sites characterized by high levels of H3K4me3, a marker of gene activity, and RNA polymerase II (Pol_II). Moreover, 70% of lipopolysaccharide (LPS)-inducible genes were found to be Jmjd3 targets. Although most Jmjd3 target genes were unaffected by its deletion, a few hundred genes, including inducible inflammatory genes, showed moderately impaired Pol_II recruitment and transcription. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analysed were uncoupled from measurable effects on this histone mark. These data show that Jmjd3 fine-tunes the transcriptional output of LPS-activated macrophages in an H3K27 demethylation-independent manner.

A new horizon for epigenetic medicine?

“…In the De Santa study [13], although TNFA was bound by JMJD3, it was not on the list of the H3K27me3-enriched genes before LPS stimulation, which could be due to H3K27me3 epitope masking. A more recent study supports the importance of the JMJD3 demethylase activity in regulating the expression of a subset of its direct target genes [15].…”

“…Intriguingly, a more recent study by De Santa et al found that in the LPS-treated macrophages, although JMJD3 binds to the TSS of many targets, most of them have no detectable H3K27me3 [13]. On some genes, the H3K27me3 level did go down in response to LPS stimulation, but it was thought to be due to nucleosome depletion [13]. Interestingly, when Kruidenier and colleagues applied the cell permeable form of GSK-J1, i.e., GSK-J4, to LPS-stimulated human primary macrophages, they found that GSK-J4 inhibited 16 of 34 LPS-induced cytokines.…”

“…In fact, one of the first reports identifying JMJD3 as a histone H3K27me3 demethylase documented a rapid JMJD3 induction by proinflammatory stimuli [12], and a follow-up study shows that JMJD3 is recruited to the transcription start sites (TSS) of the majority of lipopolysaccharide (LPS)-induced genes [13]. These studies suggest that modulating JMJD3 demethylase activity by small molecules may be one way to curtail inflammation.…”

“…Intriguingly, a more recent study by De Santa et al found that in the LPS-treated macrophages, although JMJD3 binds to the TSS of many targets, most of them have no detectable H3K27me3 [13]. On some genes, the H3K27me3 level did go down in response to LPS stimulation, but it was thought to be due to nucleosome depletion [13].…”

“…However, this possibility is complicated by a number of factors. First, the followup study suggests that regulation of npg the proinflammatory genes by JMJD3 may be independent of its demethylase activity [13]. Second, given the degree of sequence similarity among the JmjC domains of histone demethylases, it was unclear whether it is realistic to generate small molecules with sufficient substrate specificity.…”