Abstract
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.
Highlights
Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression
EHMT1 Is an H3K9-HMT That Negatively Regulates the NF-B Pathway—To test whether H3K9 methylation regulates NF-B-dependent gene expression, we silenced the expression of every known H3K9-HMT in cells using RNA interference (RNAi)
We have found that the histone methylase EHMT1 is able to negatively regulate a large fraction, but not all, of NF-B-regulated genes
Summary
Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. We report that a euchromatic H3K9 methyltransferase, EHMT1, functions as a negative regulator in both the NF-B- and type I interferon-mediated gene induction pathways. 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. Site-specific methylations of specific histone residues correlate with either activation or repression of transcription. Inducible nuclear translocation is critical for NF-B activation, many post-translational modifications have been shown to regulate the nuclear function of NF-B, including phosphorylation, ubiquitination, nitrosylation, acetylation, and methylation [16, 17]. P50 recruits EHMT1 to the promoters of genes that respond to type I interferon and represses the expression of these genes. Mechanism of EHMT1-mediated Gene Repression or EHMT1 augments interferon production and strengthens the interferon-mediated inhibition of virus replication
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