IFN-functionally resembles type I IFN, inducing antiviral protection in vitro (10,23,27) as well as in vivo (1). Activation of the IFN-receptor leads to the phosphorylation of STAT1, STAT2, and STAT3 and the formation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor (10) and to the induction of typical IFN-induced genes like the OAS and MxA genes. IFN-can reduce cell growth in vitro and possesses antitumor activity in several rodent models (11,25). However, a number of cytokines with very different biological effects activate STAT transcription factors, and pronounced functional differences between type I and type III IFNs exist. The in vivo antiviral activity of IFN-against herpes simplex virus 2 (HSV-2) has been shown to be comparable to that of IFN-␣ in a systemic model. However, a model for the clinically relevant vaginal HSV-2 infection revealed an antiviral activity of IFN-that surpassed that of IFN-␣ (1).The biological effect of the cytokine-receptor system is determined primarily by three factors: the expression profile of the cytokine itself, the expression profile of the receptor, and the set of target genes for regulation. We decided to start our investigation of the function of the IFN-system by asking which genes are regulated by IFN-. A gene array experiment covering the whole human genome revealed that all IFN--induced genes were also induced by type I IFN. Thus, no genes
Cell differentiation programs require dynamic regulation of gene expression. During meiotic prophase in Saccharomyces cerevisiae, expression of the kinetochore complex subunit Ndc80 is downregulated by a 5' extended long undecoded NDC80 transcript isoform. Here we demonstrate a transcriptional interference mechanism that is responsible for inhibiting expression of the coding NDC80 mRNA isoform. Transcription from a distal NDC80 promoter directs Set1-dependent histone H3K4 dimethylation and Set2-dependent H3K36 trimethylation to establish a repressive chromatin state in the downstream canonical NDC80 promoter. As a consequence, NDC80 expression is repressed during meiotic prophase. The transcriptional mechanism described here is rapidly reversible, adaptable to fine-tune gene expression, and relies on Set2 and the Set3 histone deacetylase complex. Thus, expression of a 5' extended mRNA isoform causes transcriptional interference at the downstream promoter. We demonstrate that this is an effective mechanism to promote dynamic changes in gene expression during cell differentiation.
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