Abstract
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.
Highlights
Many JmjC domain-containing proteins possess demethylase activity and can remove specific methyl groups on histones or other proteins
We examined whether heme modulates Gis1 transcriptional activity using a PDS element-driven lacZ reporter [24]
We found that a high level of intracellular heme was required for the activation of Gis1 transcriptional activity (Figure 1B)
Summary
Many JmjC domain-containing proteins possess demethylase activity and can remove specific methyl groups on histones or other proteins. They are dioxygenases that use ␣-ketoglutarate and Fe2+ to oxidize various substrates [1,2,3]. 32 JmjC domain-containing proteins have been identified [4] These proteins have fundamental biological functions, and their dysfunctions are implicated in many pathological processes, including developmental deficiency, cancer and cardiovascular diseases [4,5,6]. Recent epidemiological and experimental studies have implicated altered heme availability in the development and progression of an array of common human diseases, including cancer, diabetes and cardiovascular diseases [17,18]
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