Endocrine Abstracts (2012) 28 OC1.8

Metastasis related methyltransferase 1 (Merm1) /WBSCR22 regulates glucocorticoid receptor (GR) function

Maryam Jangani1,2, David Ray1 & Rachelle Donn2

1Endocrine Sciences Research Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom; 2Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom.

The metastasis related methyltransferase 1 (Merm1), originally designated WBSCR22, is implicated in cancer through H3K9 methylation and silencing of the tumour-suppressor Zac1 gene. Activated GR is a transcription factor with chromatin remodelling activity, and so the functional interaction between GR, and Merm1 was determined. Merm1 consistently potentiated GR transactivation of TAT3-Luc in HeLa cells. This was dependent on the SAM and methyltransferase domains of Merm1. Merm1 also enhanced two well-characterised GR activated genes GILZ and FKBP5. Merm1 knock-down showed a significant loss of Dex-induced transactivation of GILZ, and FKBP5, and also impaired repression of both IL-6 and IL-8. The presence of both GR and Merm1 on the GILZ promoter was confirmed using ChIP. Loss of Merm1 expression significantly reduced ligand-induced GR recruitment to the GILZ promoter. Surprisingly, loss of Merm1 expression also abolished methylation of H3 lysine4 (H3K4me3), lysine79 (H3K79me2) and lysine9 (H3K9me1) as measured by immunoblot. ChIP revealed no consistent changes for the H3K9me1, but the ligand-induced reduction in H3K79me2 was abolished, as was the induction in H3K4me3, a positive methyl mark for open chromatin. This suggests that Merm1 is required for maintenance of open chromatin at the GILZ locus to facilitate GR binding. The increase in H3K4me3, with reduction in H3K79me2 in response to GR activation by ligand, and DNA binding suggests coordinated histone modification patterns. Loss of Merm1 prevents both changes, suggesting that the driving event is the gain of methyl marks on H3K4. In conclusion, we identify Merm1 as a novel GR co-modulator, which acts on chromatin to facilitate GR binding and histone modifications, altering target gene transcription.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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