UNRAVELLING THE ROLE OF THE HISTONE DEMETHYLASE JARID1B IN MACROPHAGES

Inflammation is a fundamental response to the loss of cellular and tissue homeostasis with many important physiological roles, including host defence, tissue remodelling and repair, and the regulation of metabolism. Macrophages are not only crucial mediators of the inflammatory response, but they are also able to integrate lipid metabolism and inflammatory signalling. After an inflammatory stimulus, the expression of several hundred genes is either induced or repressed in macrophages. This complex transcriptional response consists of multiple transcriptional modules that encode different functional programmes and that are controlled by dedicated transcription factors. Post-translational modifications of histones are important determinants of transcriptional activity, and it has become evident that many chromatin modifications are extremely dynamic also in response to environmental stimuli. Among these, trimethylation of H3K4 is well conserved during evolution, and is usually associated with the 5’ ends of actively transcribed or “poised” genes. Although in the last decades the signalling pathways leading to the activation of an inflammatory response have been very well characterized, the knowledge about the tuning of this complex transcriptional network is still limited. Using a candidate approach we demonstrated that Jarid1b is transcriptionally up-regulated with a slow kinetics by LPS stimulation under the control of the transcription factor Hif1. Jarid1b is a member of the JARID1 family of H3K4 demethylases, and it has been proposed to act as transcriptional repressor, with a putative role in cell proliferation. Depletion experiments in primary macrophages suggested that Jarid1b is necessary for the activation of the master regulator of cholesterol metabolism, LXR, and the expression of its target genes, likely through the control of cellular oxysterols pools. We also generated Jarid1b knock-out mice, and performed global expression analysis in Jarid1b-deficient macrophages. The obtained data together with genomic binding analyses showed a very limited transcriptional regulatory function for Jarid1b in this cellular system. We also collected preliminary data on a possible role for Jarid1b, independent of its reported histone demethylase enzymatic activity, in regulating RNA methylation levels.