As indicated above, this review is intended to put more recent findings into a genomic context to enhance our understanding of IFN-y gene regulation through the interface between TF recruitment and chromatin structure. In this regard, the IL-12/Stat4 pathway has emerged as a critical regulator of IFN-y based in part on the fact that Stat4-deficient mice have severe deficits in IFN-y expression and Th1 development (Kaplan et al. 1996; Thierfelder et al. 1996). Stat4 is known to control IFN-y in several ways, which include binding directly to the IFN-y promoter (Nguyen et al. 2002). Stat4 is also known to recruit other transcription factors such as AP-1 to the promoter, thereby influencing IFN-y expression (Barbulescu et al. 1998; Nakahira et al. 2002). The recruitment of AP-1 and cooperative binding with Stat4 to the IFN-y promoter has been reported only in relation to IL-12/IL-18-induced synergy on IFN-y expression. AP-1, in addition to IL-18, is also a downstream target of T cell receptor (TCR) signaling, and mimicking TCR triggering has been shown to induce binding of AP-1 to the same proximal promoter sites (Penix et al. 1993, 1996). It would be interesting to determine if this Stat4-dependent mechanism of IFN-y regulation is conserved between the IL-18 receptor and TCR.

As mentioned, Stat4-dependent mechanisms are also in play with respect to chromatin remodeling events around the ifng gene (Chang and Aune 2005; Fields et al. 2002). Recently, Zhang and Boothby reported that the Switch (Swi)-sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited to the ifng gene in developing Th1 cells in a Stat4-dependent manner (Zhang and Boothby 2006). This provides a direct link between Stat4 and epigenetic alterations at the IFN-y promoter by the recruiting of a member of the Swi-SNF complex that is recognized as an important group of chromatin-modifying proteins (Narlikar et al. 2002).

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