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

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Heme, a Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins cells Article Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins Purna Chaitanya Konduri y , Tianyuan Wang y, Narges Salamat and Li Zhang * Department of Biological Sciences, University of Texas at Dallas, Mail Stop RL11, 800 W. Campbell Road, Richardson, TX 75080, USA; [email protected] (P.C.K.); [email protected] (T.W.); [email protected] (N.S.) * Correspondence: [email protected]; Tel.: +1-972-883-5757 These authors contributed equally to this paper. y Received: 7 February 2020; Accepted: 19 March 2020; Published: 22 March 2020 Abstract: 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. Keywords: Gis1; KDM4; heme; histone demethylase; protein interaction; JmjC domain 1. Introduction Histone lysyl demethylases (KDMs) play important roles in chromatin remodeling and gene regulation by catalyzing the demethylation of methylated lysine residues on the N-terminal tails of histones [1]. The majority of KDMs are JmjC domain-containing proteins, which are dioxygenases that use α-ketoglutarate and Fe2+ to oxidize various substrates [2–4]. The KDM4 family, containing five members, i.e., KDM4A-E, accepts mono-, di- and trimethylated lysines as substrates [5,6]. KDM4A/B/C (Figure1), but not KDM4D or E, contain the JmjC domain in the N-terminus as well as Tudor and plant homeodomain (PHD) domains in the C-terminus. KDM4A/B/C are widely expressed, and their orthologues are found among all vertebrates [7,8]. KDM4A/B/C share more than 50% sequence identity (Figure1) and catalyze the demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2) [3,9–13]. KDM4 proteins play important roles in diverse biological processes, including oncogenesis, inflammation, and hematopoiesis [8,14–16]. It is 2+ worth noting that the histone demethylase activity of KDM4s requires α-ketoglutarate, O2, and Fe , which are important nutritional and metabolic indicators. Thus, histone demethylase activity is linked to and is highly responsive to nutrient status [17–22]. Cells 2020, 9, 773; doi:10.3390/cells9030773 www.mdpi.com/journal/cells Cells 2020, 9, x FOR PEER REVIEW 2 of 24 Cellsα-ketoglutarate,2020, 9, 773 O2, and Fe2+, which are important nutritional and metabolic indicators. Thus, histone2 of 24 demethylase activity is linked to and is highly responsive to nutrient status [17–22]. Figure 1. The structure and alignment of Gis1 and KDM4AKDM4A/B/C/B/C domains.domains. The domains of Gis1 and KDM4s are are shown. shown. Gis1 Gis1 contains contains the the JmjN JmjN + JmjC+ JmjC (JmjN/C) (JmjN /domain,C) domain, the coiled-coil the coiled-coil domain domain (C/C), (C two/C), twoC2H2 C2H2 type typezinc zincfingers fingers (ZnFs), (ZnFs), and and two two transcr transcriptioniption activation activation domains domains (TAD1 (TAD1 and and TAD2). TAD2). KDM4AKDM4A/B/C/B/C proteins contain the JmjNJmjN/C/C domain, two PHD domains (each containing a conserved C4HC3 or C4HC2H motif), and two Tudor domains.domains. The red lines represent cysteine-proline (CP) motifs, black lines indicate the start and end of the shown domains, and the pink box in the Gis1 structure denotes the coiled-coil domain. The % amino acid identity and similarity between Gis1 and KDM4s in JmjNJmjN/C/C and zinc fingerfinger domainsdomains areare shownshown inin parentheses.parentheses. The yeast JmjC domain-containing protein Gis1 is anan orthologueorthologue ofof KDM4KDM4 proteins.proteins. Previous data, including our own recent data, showed that Gis1 possesses histone demethylase activity at H3K36 [[23–26].23–26]. In yeast,yeast, Gis1Gis1 isis oneone ofof the the key key regulators regulators mediating mediating transcriptional transcriptional reprogramming reprogramming of carbonof carbon metabolism metabolism and and stress stress responses responses during during diauxic diauxic and and post-diauxic post-diauxic shifts shifts [[27–32].27–32]. Gis1Gis1 binds to the post-diauxic shift (PDS) DNA DNA element element and and ca cann both both activate activate and and repress repress transcription transcription [33–35].[33–35]. It acts downstream of TOR, RASRAS/cAMP,/cAMP, andand AKTAKT/Sc/Sch9h9 signalingsignaling pathways in response to nutrient status [[28,30,32].28,30,32]. Gis1Gis1 containscontains multiple multiple domains, domains, including including a JmjNa JmjN region, region, a JmjC a JmjC region, region, a coiled-coil a coiled- domain,coil domain, two two C2H2 C2H2 type type zinc zinc fingers fingers (ZnFs), (ZnFs), and and two two transcription transcription activationactivation domains (TADs) (TADs) (Figure1 1))[ [30,36,37].30,36,37]. JmjN JmjN and and JmjC JmjC interact interact physica physicallylly to form to form a structural a structural unit unit or a ordomain a domain [37]. [The37]. TheJmjN/C JmjN domain/C domain presumably presumably confers confers histone histone demethylase demethylase activity, activity, but but is is dispensable dispensable for transcriptional activation activation by by Gis1 Gis1 [36]. [36]. This This Gis1 Gis1 JmjN/C JmjN/ Cdomain domain is ishighly highly homologous homologous to tothose those of ofKDM4A/B/C, KDM4A/B/C, while while the the C-terminal C-terminal regions regions of of Gis1 Gis1 and and KDM4A/B/C KDM4A/B/C share share low low homology homology (Figure (Figure 11).). The Gis1 zinc fingersfingers allow Gis1 to bind to DNA an andd regulate transcription [[30,36,37].30,36,37]. The C-terminal regions of KDM4AKDM4A/B/C/B/C proteins contain two PHDsPHDs and twotwo TudorTudor domainsdomains (Figure(Figure1 ).1). TheThe PHDPHD domain is a protein module containing ~50 amino acid residues with a conserved C4HC3 or C4HC2H motif that coordinates two zinc ions in a cross-brace configurationconfiguration [[38].38]. The Tudor domain typically contains ~60 amino amino acids acids that that comprise comprise 4–5 4–5 antiparallel antiparallel ββ-strands-strands to to form form a a barrel-like barrel-like structure structure [39]. [39]. Both PHDPHD and and Tudor Tudor domains domains are histoneare histone reader reader domains domains that recognize that recognize post-translationally post-translationally modified histones,modified suchhistones, as methylated such as methylated H3 [40–43 ].H3 Although [40–43]. Although the JmjN/C the domains JmjN/C of domains Gis1 and of KDM4s Gis1 and are KDM4s highly conserved,are highly conserved, the C-terminal the C-terminal domain sequences domain sequen of Gis1ces are of quite Gis1 di arefferent, quite anddifferent, there isand no there homology is no betweenhomology the between TADs of the Gis1 TADs and of the Gis1 corresponding and the corresp regionsonding of KDM4s regions (Figure of KDM4s1). Thus, (Figure we do 1). not Thus, expect we thatdo not KDM4s expect can that substitute KDM4s can for Gis1substitute in yeast. for Gis1 in yeast. Interestingly, ourour recentrecent studiesstudies showedshowed thatthat hemeheme promotespromotes both transcriptionaltranscriptional and histone demethylase activities of Gis1 [23]. [23]. Heme Heme can can bind bind to to both both the the JmjN/C JmjN/C and ZnF domains, however, however, heme binding to the JmjN/C JmjN/C domain is not necessary for heme regulation regulation of Gis1 Gis1 activity. activity. In In contrast, contrast, heme binding to the ZnF domain promotes heme activation of both transcriptional and histone demethylase activities [23]. Under heme-deficient conditions, Gis1 is free of heme and is inactive. Its Cells 2020, 9, 773 3 of 24 activities are repressed by the ZnF domain, which likely cooperates with other cellular proteins. When heme levels increase, heme binds to the JmjN/C and ZnF domains, presumably causing other cellular proteins to dissociate from Gis1 and alter Gis1 conformation, thereby leading to full activation of Gis1 transcriptional and demethylase activities. Heme acts as a prosthetic group or cofactor in proteins and enzymes required for oxygen utilization and metabolism, such as globins and cytochromes [44–47]. Heme serves as a signaling molecule regulating diverse processes ranging from gene transcription
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  • Genome-Wide Screen of Cell-Cycle Regulators in Normal and Tumor Cells
    bioRxiv preprint doi: https://doi.org/10.1101/060350; this version posted June 23, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion Maria Sokolova1, Mikko Turunen1, Oliver Mortusewicz3, Teemu Kivioja1, Patrick Herr3, Anna Vähärautio1, Mikael Björklund1, Minna Taipale2, Thomas Helleday3 and Jussi Taipale1,2,* 1Genome-Scale Biology Program, P.O. Box 63, FI-00014 University of Helsinki, Finland. 2Science for Life laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, SE- 141 83 Stockholm, Sweden. 3Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden To identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells.
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