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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.

Original publication

DOI

10.1074/jbc.M113.540906

Type

Journal article

Journal

J Biol Chem

Publication Date

28/03/2014

Volume

289

Pages

8931 - 8946

Keywords

Glucocorticoid Receptor, Glucocorticoids, Histone Methylation, Inflammation, Interferon, Lung, Tumor Necrosis Factor (TNF), Ubiquitination, B-Lymphocytes, Bronchi, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Chromatin Assembly and Disassembly, Epithelium, Gene Expression Regulation, Neoplastic, Glucocorticoids, Histones, Humans, Inflammation, Interferon-gamma, Lung Neoplasms, Lysine, Methylation, Methyltransferases, Protein Binding, Protein Kinases, Protein Structure, Tertiary, RNA, Messenger, Receptors, Glucocorticoid, Signal Transduction, Transcriptional Activation, Tumor Necrosis Factor-alpha, Ubiquitination