Heme is an important signaling molecule that mediates the effect of oxygen on several cellular processes. In yeast, heme serves as a secondary messenger of oxygen as production of heme requires oxygen. Gis1 is a transcription factor containing the highly conserved JmjC domain. JmjC domain containing proteins belong to JHDM3/JMJD2 subfamily (lysine-specific) of histone demethylases which can function as oxygen sensors. Studies in our lab has shown that Gis1 is regulated by oxygen and heme. Protein localization studies showed that under hypoxia Gis1 is retained in the cytoplasm and oxygen is required for the nuclear localization of Gis1. Interestingly, a putative heme-responsive cysteine-proline sequence (CP motif) is present in the JmjC domain. Upon further investigation, we found that Gis1 binds heme directly, and its transcriptional activity is regulated by heme levels in the cell. Further work is being carried out to pinpoint the domain(s) mediating the effect of heme on the transcriptional activity of Gis1. Additionally Gis1 has a paralog, Rph1 which also contains the JmjC domain. Gis1 and Rph1 are 34% similar, and their zinc finger domains are almost identical. Rph1 is a repressor of autophagy-related genes in nutrient-rich conditions, which is independent of its histone demethylase activity. It is also a repressor of DNA repair gene PHR1. We are investigating if Rph1 is also regulated by heme.