The yeast GIS1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of GIS1 transcriptional and histone demethylase activities. We found that two GIS1 modules, the JmjN + JmjC domain and the zinc finger (ZnF), can bind to heme specifically in vitro. In vivo functional analysis showed that the ZnF, not the JmjN + JmjC domain, promotes heme activation of transcriptional activity. Likewise, measurements of the demethylase activity of purified GIS1 proteins showed that full-length GIS1 and the JmjN + JmjC domain both possess demethylase activity. However, heme potentiates the demethylase activity of full-length GIS1, but not that of the JmjN + JmjC domain, which can confer heme activation of transcriptional activity in an unrelated protein. These results demonstrate that GIS1 represents a novel class of multi-functional heme sensing and signaling proteins, and that heme binding to the ZnF stimulates GIS1 demethylase and transcriptional activities.

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Journal Article | Research Support, N.I.H., Extramural

Authors

Lal S, Comer JM, Konduri PC, Shah A, Wang T, Lewis A, Shoffner G, Guo F, Zhang L

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