STAT4 is phosphorylated in response to interleukin-12 and is essential for IL12 signal transduction. For further information on STATs. STAT4 and STAT1, which both map to chromosome 2q32, may have arisen via a tandem gene duplication. However, STAT1 was expressed ubiquitously, whereas STAT4 was expressed in specific tissues, including spleen, heart, brain, peripheral blood cells, and testis. STAT4 expression was drastically increased in T cells following treatment with a DNA methyltransferase inhibitor. Truncation of methylation sites in the proximal regulatory elements of the STAT4 promoter markedly enhanced transcriptional activity. The N-terminal protein interaction domain (N domain) of STAT4 is required for STAT4 activation after IL12 signaling.