Endocrine Abstracts

Variation in glucocorticoid (Gc) sensitivity underlies metabolic disease, and affects therapeutic response in inflammation. Using an in-vitro screening approach we identify two new mechanisms capable of regulating Gc sensitivity.

The first involves interferon induced factor 16 (IFI16). IFI16 potentiated both transactivation, and Gc repression of NFκB. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand dependent repression of GR expression, or the ligand dependent induction of GR phosphorylation. Co-immunoprecipitation revealed an interaction, suggesting IFI16 modulation of GR function is mediated by protein cross-talk. Transfection analysis with GR mutants showed that the ligand binding domain of GR binds IFI16, and is the target domain for IFI16 regulation.

The second mechanism involves Merm1, a histone methyltransferase, which potentiates GR transactivation through its SAM and methyltransferase domains. Merm1 is required for maintenance of an active chromatin methyl mark (H3K79me2) at the GREs and facilitates GR binding. Activated GR promotes H3K4me3, and represses H3K79me2 marks at GREs, in a Merm1 dependent manner, suggesting coordinated histone modification whereby one change influences the other. Inflammation causes glucocorticoid resistance, which is replicated in-vitro by the combined action of inflammatory cytokines TNFα, and IFNγ. These cytokines suppress Merm1 protein, impair GR recruitment to GREs, and inhibit acquisition of the H3K4me3 mark. Glucocorticoid sensitivity was rescued by restoring Merm1 expression.

In conclusion, IFI16 is a novel modulator of GR function, acting through the GR ligand binding domain, and Merm1 regulates chromatin structure so affecting GR recruitment, GR function, and mediates cytokine-induced cellular glucocorticoid resistance.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.