STAT3-driven transcription depends upon the dimethylation of K49 by EZH2.

Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers.

Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3.

STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function.

Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes.

Following its tyrosine phosphorylation, STAT3 is methylated on K140 by the histone methyl transferase SET9 and demethylated by LSD1 when it is bound to a subset of the promoters that it activates. Methylation of K140 is a negative regulatory event, because its blockade greatly increases the steady-state amount of activated STAT3 and the expression of many (i.e.

Transposon-based mutagenesis identifies short RIP1 as an activator of NFkappaB.

We used a vector based on the Sleeping Beauty transposon to search for constitutive activators of NFkappaB in cultured cells. Dominant mutations were produced by random insertion of a tetracycline-regulated promoter, which provided robust and exceptionally well-regulated expression of downstream genes. The ability to regulate the mutant phenotype was used to attribute the latter to the insertional event.