Abstract
Glucocorticoids (GC) regulate cell fate and immune function. We identified the metastasis-promoting methyltransferase, metastasis-related methyltransferase 1 (WBSCR22/Merm1) as a novel glucocorticoid receptor (GR) regulator relevant to human disease. Merm1 binds the GR co-activator GRIP1 but not GR. Loss of Merm1 impaired both GR transactivation and transrepression by reducing GR recruitment to its binding sites. This was accompanied by loss of GR-dependent H3K4Me3 at a well characterized promoter. Inflammation promotes GC resistance, in part through the actions of TNFα and IFNγ. These cytokines suppressed Merm1 protein expression by driving ubiquitination of two conserved lysine residues. Restoration of Merm1 expression rescued GR transactivation. Cytokine suppression of Merm1 and of GR function was also seen in human lung explants. In addition, striking loss of Merm1 protein was observed in both inflammatory and neoplastic human lung pathologies. In conclusion, Merm1 is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease.
Highlights
Glucocorticoid (GC) action in inflammation is important but poorly understood
It has been recognized that the actions of the glucocorticoid receptor (GR) to regulate target gene transcription are, in part, mediated by directed chromatin remodeling, with resulting changes in the access to, and binding of other transcription factors (15, 40 – 43)
Most recently it has become clear that GR and other transcription factors may associate with their binding sites in a highly dynamic state (44 – 46)
Summary
Glucocorticoid (GC) action in inflammation is important but poorly understood. Results: Merm regulates glucocorticoid receptor (GR) recruitment to the genome and mediates subsequent histone modification. Inflammation promotes GC resistance, in part through the actions of TNF␣ and IFN␥ These cytokines suppressed Merm protein expression by driving ubiquitination of two conserved lysine residues. Merm is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease. We have identified the WBSCR22/metastasis-related methyltransferase 1 (Merm1) gene as an important regulator of GR binding and function and a mediator of cytokine-induced glucocorticoid resistance. More recently Merm was identified in a genetic screen for genes promoting cancer metastases by inhibiting Zac1-mediated p53-dependent apoptosis [26] This action required methylation of histone H3 lysine 9 (H3K9) at the Zac locus, thereby rendering a transcriptionally repressive chromatin environment. High level Merm expression was found in the bronchial epithelium but was significantly impaired in a broad range of pulmonary inflammatory and neoplastic diseases
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