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Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins

Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA
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Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cells 2020, 9(3), 773; https://doi.org/10.3390/cells9030773
Received: 7 February 2020 / Revised: 18 March 2020 / Accepted: 19 March 2020 / Published: 22 March 2020
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation. View Full-Text
Keywords: Gis1; KDM4; heme; histone demethylase; protein interaction; JmjC domain Gis1; KDM4; heme; histone demethylase; protein interaction; JmjC domain
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Konduri, P.C.; Wang, T.; Salamat, N.; Zhang, L. Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins. Cells 2020, 9, 773.

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