H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response.
Transcriptional homeostasis relies on the balance between positive and negative regulation of gene transcription. Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. Here, we report that a euchromatic H3K9 methyltransferase, EHMT1, functions as a negative regulator in both the NF-κB- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-κB target genes. Moreover, EHMT1 interacts with p50, and, surprisingly, p50 appears to repress the expression of type I interferon genes and genes activated by type I interferons by recruiting EHMT1 to catalyze H3K9 methylation at their promoter regions. Silencing the expression of EHMT1 by RNA interference enhances expression of a subset NF-κB-regulated genes, augments interferon production, and augments antiviral immunity.
H3K4 trimethylation is strongly associated with active transcription. The deposition of this mark is catalyzed by SET-domain methyltransferases, which consist of a subcomplex containing WDR5, ASH2L, and RBBP5 (the WAR subcomplex); a catalytic SET-domain protein; and additional complexspecific subunits. The ERK MAPK pathway also plays an important role in gene regulation via phosphorylation of transcription factors, co-regulators, or histone modifier complexes. However, the potential interactions between these two pathways remain largely unexplored. We investigated their potential interplay in terms of the regulation of the immediate early gene (IEG) regulatory network. We found that depletion of components of the WAR subcomplex led to increased levels of unspliced transcripts of IEGs that did not necessarily reflect changes in their mature transcripts. This occurs in a manner independent from changes in the H3K4me3 levels at the promoter region. We focused on FOS and found that the depletion of WAR subcomplex components affected the efficiency of FOS transcript processing. Our findings show a new aspect of WAR subcomplex function in coordinating active transcription with efficient pre-mRNA processing.