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EHMT1 protein binds to nuclear factor-?B p50 and represses gene expression.

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-?B- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-?B 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-?B-regulated genes, augments interferon production, and augments antiviral immunity.

SUBMITTER: Ea CK

PROVIDER: S-EPMC3438952 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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EHMT1 protein binds to nuclear factor-κB p50 and represses gene expression.

Ea Chee-Kwee CK Hao ShengLi S Yeo Kok Siong KS Baltimore David D

The Journal of biological chemistry 20120716 37

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, ...[more]

PMID: 22801426

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Project description:Adenosine promotes cytoprotection under conditions of infection, ischemic preconditioning and oxidative stress. Previous studies from our laboratory indicate that the expression of the adenosine A1 receptor (A1AR) is induced by oxidative stress via activation of nuclear factor (NF)-kappaB. The prototypic transcription factor is composed of homo- or heterodimers of p50 and p65 subunits. To determine the role of NF-kappaB in the regulation of the A1AR in vivo, we compared the A1AR RNA and protein levels in the brains of mice lacking the p50 subunit of NF-kappaB (p50-/- mice) and age-matched B6129PF2/J (F2) controls. Radioligand binding assays in the cortex revealed a significantly lower number of A(1)AR (maximal binding capacity, Bmax) in the cortex of p50-/- mice (151+/-62 fmol/mg protein) versus 479+/-181 fmol/mg protein in the F2 (N=5 per strain, P<0.05), but no change in the equilibrium dissociation constant. Similar reductions in A1AR were measured in the hippocampus, brain stem and hypothalamus and in peripheral tissues, such as the adrenal gland, kidney and spleen. Estimation of the A1AR following purification by antibody affinity columns also indicated reduced A1AR in the p50-/- mice cortex, as compared with the F2 mice. A1AR immunocytochemistry indicates distinct neuronal labeling in the F2 cortex, which was substantially reduced in similar sections obtained from p50-/- mice. The p50-/- mice expressed lower levels of A1AR mRNA than F2 mice, as determined by real time PCR. Quantitation of the A1AR transducing G proteins by Western blotting show significantly less Galphai3, no change in Galphai1, but higher levels of Galphao and Gbeta in the cortices of p50-/-, as compared with F2 mice. Administration of bacterial lipopolysaccharide (LPS), an activator of NF-kappaB, increased A1AR expression in the cortices of F2 mice but not p50-/- mice. Cortical neurons cultures prepared from p50-/- mice showed a greater degree of apoptosis, compared with neurons from F2 mice. Activation of the A1AR reduced apoptosis with greater efficacy in cultures from F2 than p50-/- mice. Taken together, these data support a role for NF-kappaB in determining both the basal and LPS-stimulated A1AR expression in vivo which could contribute to neuronal survival.

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EHMT1 protein binds to nuclear factor-?B p50 and represses gene expression.

Publications

EHMT1 protein binds to nuclear factor-κB p50 and represses gene expression.

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