Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway

Abstract

STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response and adaptive immunity. They associate with IFN regulatory factor 9 (IRF9) to form a heterotrimeric transcription factor complex known as ISGF3. The regulation of IFN-stimulated gene (ISG) expression has served as a model of JAK-STAT signaling and mammalian transcriptional regulation, but to date has primarily been analyzed at the single gene level. While many aspects of ISGF3-mediated gene regulation are thought to be common features applicable to several ISGs, there are also many reports of distinct cases of non-canonical STAT1 or STAT2 signaling events and distinct patterns of co-regulators that contribute to gene-specific transcription. Recent genome-wide studies have begun to uncover a more complete profile of ISG regulation, moving toward a genome-wide understanding of general mechanisms that underlie gene-specific behaviors.

Keywords: STAT1; STAT2; genome-wide; interferon; transcriptional regulation.

Figure 1. Diagrammatic representation of transcription regulation in response to IFN stimulation. (A) Binding of type I or type III IFN to their cognate receptors initiates a signaling cascade that results in phosphorylation and heterodimerization of STAT1 and STAT2 and association with IRF9 to form the active transcription factor complex ISGF3. (B) STAT1 and STAT2 primarily associate to form ISGF3, but have also been reported to form other transcription factor complexes in response to IFN stimulation. These include AAF/GAF, U-STAT1, a STAT2/IRF9 complex, and ISGF3^II. AAF/GAF has been widely reported to form in response to IFNα stimulation but the other complexes are less well understood. Accumulation of U-STAT1 has been shown to regulate ISG transcription; however, the structure and composition of the active transcription factor are not yet known. A STAT2/IRF9 complex has been reported to be transcriptionally active when overexpressed and ISGF3^II has been identified in a single cell line. (C) ISGF3, the canonical transcription factor, regulates the transcription of many ISGs. However, the co-regulators necessary for gene expression vary from gene to gene. Three ISGs, ISG54, 9–27, and ISG15, are depicted here along with their gene-specific co-regulators as examples of the differential regulation in the IFN pathway.

Figure 2. ChIP-seq profile at ISG54, RUTBC3 and an unannotated locus. Sequence tag density signals from ENCODE ChIP-seq data sets are shown for untreated, 30 min IFNα-stimulated or 6 h IFNα-stimulated K562 cells (black) and GM12878 cells (gray). STAT1 and STAT2 occupancy is shown in the top portion at ISG54, a classical ISG (A), RUTBC3, a gene upregulated by IFNα (B) and an unannotated locus on chromosome 2 at position 146 449 900–146 451 900 (C). Co-occupancy at these loci by IRF1, c-Myc and c-Jun, is shown in the bottom portion of the figure. The individual tracks were auto-scaled to allow visualization of the binding pattern, especially when the signal differs drastically between loci. *Indicates data was not generated from the same experiment as the IFNα-stimulated data.