THE ROLE OF HISTONE DEMETHYLASE JMJD3 IN THE INFLAMMATORY RESPONSE: GENERATION AND ANALYSIS OF IN VIVO MODELS

Jmjd3, a JmjC family histone demethylase, is quickly induced by the transcription factor NF- kB in response to microbial stimuli. Jmjd3 erases trimethylated lysine 27 in histone H3 (H3K27me3), a histone mark associated with transcriptional repression and involved in lineage determination, differentiation and tissue homeostasis. However, the specific contribution of Jmjd3 induction and H3K27me3 demethylation to innate immunity and inflammation remains unknown. To define this role, we generated gene-targeted mice lacking histone demethylase using standard protocol to see the effect of this specific Histone demethylase depletion on all tissues and in particular in immune system to understand the biological functions of jmjd3 in inflammatory responses.. Strikingly, transcription of most Jmjd3 target genes was unaffected by its deletion, a few hundred genes including IL12b and Ccl5 showed mild to moderate mRNA changes associated with impaired transcription; however, no gene was completely dependent on Jmjd3 for induction. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and the transcriptional effects of Jmjd3 absence in the window of time analyzed were uncoupled from measurable effects on this histone mark. Overall, these data demonstrate that Jmjd3 participates in fine- tuning the transcriptional output of LPS-activated macrophages in a manner that is largely independent of H3K27me3 demetylation.