Lal, SnehaComer, Jonathan M.Konduri, Purna C.Shah, AjitWang, TianyuanLewis, AnthonyShoffner, GrantGuo, FengZhang, Li2018-10-222018-10-222017-11-062018-10-221362-4962http://hdl.handle.net/10735.1/6214The 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.enCC BY 4.0 (Attribution)©2017 The Authorshttp://creativecommons.org/licenses/by/4.0/GIS1 protein, S cerevisiaeHistone DemethylasesJumonji C domainJumonji Domain-Containing Histone DemethylasesarticleLal, Sneha, Jonathan M. Comer, Purna C. Konduri, Ajit Shah, et al. 2018. "Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family" Nucleic Acids Research 46(1), doi:10.1093/nar/gkx1051461