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Department of Pharmacology

Department of Pharmacology
 

Contact Information:

University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-South
12801 East 17th Ave
Aurora CO 80045

Phone: (303) 724-3593
Fax: (303) 724-3663
E-mail: tatiana.kutateladze@ucdenver.edu
curriculum vitae

Affiliated Programs

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Research in my group focuses on the molecular mechanisms of epigenetic regulation and phosphoinositide signaling. We apply high field NMR spectroscopy, X-ray crystallography and a wide array of biochemical and molecular biology approaches to characterize the atomic-resolution structures and functions of chromatin- and lipid-binding proteins implicated in cancer and other human diseases.

The study of epigenetics and deciphering the ‘epigenetic code/language’ is the major direction in the lab. The genetic material of eukaryotic cells is packaged into the nucleus in the form of chromatin. Chromatin is made up of building blocks called nucleosomes. Each nucleosomal particle contains an octamer of four histone proteins, H2A, H2B, H3 and H4, around which genomic DNA is wound almost twice. The nucleosomes undergo recurrent structural rearrangements and are subject to posttranslational modifications (PTMs). A particularly large number of PTMs, or epigenetic marks, have been identified on the histone tails that protrude from the nucleosomal core and are freely accessible to histone acetyltransferases (HATs), histone deacetylases (HDACs), histone lysine methyltransferases (HKMTs), kinases, phosphatases and other enzymes capable of depositing or removing PTMs. The list of PTMs is expanding rapidly and includes, among others, acetylation and methylation of lysine residues, methylation of arginine residues, and phosphorylation of serine and threonine residues.

The histone PTMs are recognized by protein modules, referred to as epigenetic effectors, histone-binding domains or simply PTM ‘readers’. Binding of the effectors recruits various components of the epigenetic machinery to chromatin, mediating fundamental processes such as gene transcription, DNA replication and recombination, DNA damage response and chromatin remodeling. Chromatin-associating complexes often contain multiple readers within one or several subunits that show specificities for distinct PTMs. Coordinated recognition of a combination of PTMs can provide a lock-and-key type mechanism for targeting a particular genomic site and ensuring proper biological outcomes. The intricate relationship among the epigenetic components represents one of the most intriguing concepts in modern chromatin biology, which we have only begun to explore. Clearly, the spatial and temporal modulation of and crosstalk between histone PTMs, the PTM-writing, -erasing and -reading proteins play a crucial role in defining the epigenetic landscape.

Misreading of epigenetic marks has been linked to a host of human diseases including autoimmune and developmental abnormalities, addiction, schizophrenia and cancer. Thus, understanding the molecular mechanisms and functional importance of reader-PTM interactions is essential to understanding not only the basic principles of epigenetic regulation, but also the etiology of epimutation-induced human diseases. Our goal is to structurally characterize PHD fingers, Tudor, MBT and other epigenetic effectors and to establish the significance of reading of the epigenetic marks (Fig. 1).  

Another research direction is aimed at elucidating the mechanisms of membrane anchoring by PI-binding proteins (Fig. 2). PIs are generated through mono-, bis- and tris-phosphorylation of the inositol headgroup of PtdIns. Each PI has a unique stereochemistry and is involved in distinct biological responses. Collectively, seven known PI isoforms create a remarkably complex signaling network, which could be viewed through a ‘PI code’ model. The level and activity of PIs are tightly regulated by PI kinases, phosphatases and phospholipases that either initiate or terminate signaling cascades by phosphorylating, dephosphorylating and hydrolyzing PIs. Individual PIs are highly concentrated in different intracellular membranes, such as the plasma membrane, or membranes of early endosomes, multivesicular bodies and Golgi. PIs form specific docking sites for lipid-binding effectors, including the ANTH, ENTH, FYVE, PH and PX domain-containing proteins. Interactions of these domains with PIs are required for many fundamental processes including growth, differentiation, vesicular trafficking, cytoskeletal rearrangement and survival of cells. Many PI-binding proteins are involved in down-regulation of proliferative pathways through internalizing oncogenic growth factor receptors. We are interested in defining the molecular basis of activation and recruitment of the PI-binding proteins to the membranes.

Current Lab Members 

 

Past Trainees 

 

 

Dr. Kutateladze's Publications on PubMed​

Selected Recent Publications:  

Peña, P. V., Davrazou, F., Shi, X., Walter, K., Verkhusha, V. V., Gozani, O., Zhao, R. and Kutateladze, T.G.  Molecular mechanism of histone H3K4Me3 recognition by Plant Homeodomain of ING2 tumor suppressor, Nature, 442, 100-3 (2006).

Shi, X., Hong, T., Walter, K. L., Ewalt, M., Michishita, E., Hung, T., Carney, D., Peña, P.V., Lan, F., Kaadige, M. R., Lacoste, N., Cayrou, C., Davrazou, F., Saha, A., Cairns, B. R., Ayer, D. E., Kutateladze, T. G., Shi, Y., Côté, J., Chua, K. F. and Gozani, O. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression, Nature, 442, 96-9 (2006).

Chen, Z., Zang, J., Whetstine, J., Hong, X., Davrazou, F., Kutateladze, T. G., Mao, Q., Pan, C., Dai, S., Shi, Y. and Zhang, G.  Crystal structure of the catalytic core domain of a novel histone demethylase, Cell, 125, 691-702 (2006).

Lee, S.A., Kovacs, J., Stahelin, R., Cheever, M.L., Overduin, M., Setty, T.G., Burd, C., Cho, W. and Kutateladze, T.G. Molecular mechanism of membrane docking by the Vam7p PX domain, J. Biol. Chem., 281, 37091-101 (2006).

Xu, Y., Lee, S.A., Kutateladze, T.G., Sbrissa, D., Shisheva, A. and Prestwich, G.D. Chemical synthesis and molecular recognition of phosphatase-resistant analogues of phosphatidylinositol-3-phosphate, J. Am. Chem. Soc., 128, 885-97 (2006).

Kutateladze, T.G. Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain, BBA-Mol. Cell. Biol. Lipids, 1761, 868-77 (2006).

Gajewiak, J., Xu, Y., Lee, S. A., Kutateladze, T. G. and Prestwich, G. D. Synthesis and Molecular Recognition of Phosphatidylinositol-3-methylenephosphate, Org. Letters, 8, 2811-3 (2006).

Shi X., Kachirskaia I., Walter K.L., Kuo J.H., Lake A., Davrazou F., Chan S.M., Martin D.G., Fingerman I.M., Briggs S.D., Howe L., Utz P.J., Kutateladze T.G., Lugovskoy A.A., Bedford M.T. and Gozani O. Proteome-wide analysis in S. cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem., 282, 2450-5 (2007).

Huang, W., Zhang, H., Davrazou, F., Kutateladze, T.G., Shi, X., Gozani, O. and Prestwich, G.D. Stabilized Phosphatidylinositol-5-Phosphate Analogues as Ligands for the Nuclear Protein ING2: Chemistry, Biology and Molecular Modeling. J. Am. Chem. Soc., 129, 6498-6506 (2007).

Kutateladze, T.G. Mechanistic similarities in docking of the FYVE and PX domains to PI3P-containing membranes. Prog. Lipid Res., 46, 315-27 (2007).

Hom, R.A., Vora, M., Regner, M., Subach, O.M., Cho, W., Verkhusha, V.V., Stahelin, R. and Kutateladze, T. G. pH-Dependent Binding of the Epsin ENTH Domain and the AP180 ANTH Domain to PI(4,5)P2- containing Bilayers. J. Mol. Biol., 373, 412-23 (2007).

Matthews, A.G.W., Kuo, A., Ramon-Maiques S., Han, S., Champagne, K.S., Gallardo, M., Carney, D., Cheung, P., Ciccone, D.N., Walter, K.L., Utz, P.J., Shi, Y., Kutateladze, T.G., Yang, W., Gozani, O. and Oettinger, M.A. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature, 450, 1106-10 (2007).

Champagne, K.S., Saksouk, N., Peña, P.V., Johnson, K., Ullah, M., Yang, X.J., Côte, J. and Kutateladze, T.G. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins, 72, 1371-6 (2008).

He, J., Haney, R.M., Vora, M., Verkhusha, V.V., Stahelin, R.V. and Kutateladze, T.G. Molecular mechanism of membrane targeting by GRP1 PH domain. J. Lipid Res., 49, 303-12 (2008) (featured on cover).

Peña, P. V., Hom, R.A., Hung, T., Lin, H., Kuo, A.J., Wong, R.PC., Subach, O.M., Champagne, K.S., Zhao, R., Verkhusha, V.V., Li, G., Gozani, O. and Kutateladze, T. G. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol., 380, 303-12 (2008).

Peña, P. V., Musselman, C.A, Kuo, A.J., Gozani, O. and Kutateladze, T. G. NMR assignments and histone specificity of the ING2 PHD finger. Mag. Res. Chem., 47, 352-8 (2009).

Champagne, K.S. and Kutateladze, T.G. Structural insight into histone recognition by the ING PHD fingers, Curr. Drug Targets, 5, 432-41 (2009).

He, J., Vora, M., Haney, R.M., Filonov, G.S., Musselman, C.A., Burd, C.G., Kutateladze, A.G., Verkhusha, V.V., Stahelin, R.V. and Kutateladze, T.G. Membrane insertion of the FYVE domain is modulated by pH. Proteins, 76, 852-60 (2009).

Hung, T., Binda, O., Champagne, K.S., Kuo, A.J., Johnson, K., Chang, H.Y., Simon, M.D., Kutateladze, T.G. and Gozani, O. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol. Cell, 33, 248-56 (2009).

Saksouk, N., Avvakumov, N., Champagne, K.S., Hung, T., Doyon, Y., Cayrou, C., Ulla, M., Landry, A.J., Cote, V., Yang, X.J., Gozani, O., Kutateladze, T.G. and Côte, J. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol. Cell, 33, 257-65 (2009).

Musselman, C.A., Mansfield, R.E., Garske, A.L., Davrazou, F., Kwan, A., Oliver, S.S., OLeary, H., Denu, J.M., Mackay, J.P. and Kutateladze, T.G. Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications, Biochem. J., 423, 179-87 (2009).

Musselman, C.A. and Kutateladze, T.G. PHD fingers: epigenetic effectors and potential drug targets, Mol. Interv., 9, 314-23 (2009).

Zhang, H., He, J., Kutateladze, T.G., Sakai, T., Sasaki, T., Markadieu, N., Erneux, C. and Prestwich, G.D. 5-Stabilized phosphatidylinositol 3,4,5-trisphosphate analogues bind Grp1 PH, inhibit phosphoinositide phosphatases, and block neutrophil migration, ChemBioChem, 11, 388-395 (2010).

Garske, A.L., Oliver, S.S., Wagner, E.K., Musselman, C.A., LeRoy, G., Garcia, B.A., Kutateladze, T.G. and Denu, J.M. Combinatorial profiling of chromatin-binding modules reveals multi-site discrimination for posttranslational modifications, Nature Chem. Biol., 6, 283-90 (2010).

Roy, S., Musselman, C.A., Kachirskaia, I., Hayashi, R., Glass, K.C., Nix, J.C., Gozani, O., Appella, E., and Kutateladze, T.G. Structural insight into p53 recognition by the 53BP1 tandem Tudor domain, J. Mol. Biol., 398, 489-96 (2010).

Chang, P.Y., Hom, R.A., Musselman, C.A., Zhu, L., Kuo, A., Gozani, O., Kutateladze, T.G. and Cleary, M.L. Binding of the MLL PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription, J. Mol. Biol., 400, 137-144 (2010) (featured on cover).

Hom, R.A., Chang, P.Y., Roy, S., Musselman, C.A., Glass, K.C., Selezneva, A.I., Gozani, O., Ismagilov, R.F., Cleary, M.L. and Kutateladze, T.G. Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain, J. Mol. Biol. 400, 145-54 (2010) (featured on cover).

West, L.E., Roy, S., Lachmi-Weiner, K., Hayashi, R., Shi, X., Appella, E., Kutateladze, T.G. and Gozani, O. The MBT repeats of L3MBTL1 link SET8 mediated p53 methylation at lysine 382 to target gene repression, J. Biol. Chem., 285, 37725-32 (2010).

Kutateladze, T.G. Translation of the phosphoinositide code by PI effectors, Nature Chem. Biol., 6, 507-13 (2010).

Mansfield, R.E., Musselman, C.A., Kwan, A., Oliver, S.S., Garske, A.L., Davrazou, F., Denu, J.M., Kutateladze, T.G. and Mackay, J.P. The PHD fingers of CHD4 are histone H3-binding modules with preference for unmodified H3K4 and methylated H3K9, J. Biol. Chem., 286, 11779-91 (2011).

Musselman, C.A. and Kutateladze, T.G. Methyl fingerprinting of the nucleosome reveals the molecular mechanism of high-mobility group nucleosomal2 association, Proc. Natl. Acad. Sci. USA, 108, 12189-90 (2011).

Lumb, C.N., He, J., Xue, Y., Stansfeld, P.J., Stahelin, R.V., Kutateladze, T.G. and Sansom, M.S.P. Biophysical and computational studies of membrane penetration by the GRP1 pleckstrin homology domain, Structure, 19, 1338-46 (2011).

He, J., Scott, J.L., Heroux, A., Roy, S., Lenoir, M., Overduin, M., Stahelin, R.V. and Kutateladze, T.G. Molecular basis of phosphatidylinositol 4-phosphate and ARF1 recognition by FAPP1 PH domain. J. Biol. Chem., 286, 18650-7 (2011).

Kutateladze, T.G. Snapshot: histone readers, Cell, 146, 842 (2011).

Musselman, C.A. and Kutateladze, T.G. Handpicking epigenetic marks with PHD fingers, Nucl. Acids Res., 39, 9061-71 (2011).

He, J., Gajewiak, J., Scott, J.L., Gong, D., Ali, M., Best, M.D., Prestwich, G. D., Stahelin, R.V. and Kutateladze, T.G.  Metabolically stabilized derivatives of phosphatidylinositol 4-phosphate: synthesis and applications, Chem. Biol. 18, 1312-9 (2011).

Kutateladze, T.G. IP4 is an epigenetic coregulator. Nature Chem. Biol., 8, 230-1 (2012).

Yuan, C.C., Matthews, A.G.W., Jin, Y., Chen, C.F., Chapman, B.A., Ohsumi, T.K., Glass, K.C., Kutateladze, T.G., Borowsky, M.L., Struhl, K. and Oettinger, M.A. Histone H3R2 symmetric dimethylation and histone H3K4 trimethylation are tightly correlated in eukaryotic genomes. Cell Reports, 1, 83-90 (2012).

Kutateladze, T.G. Molecular analysis of protein-phosphoinositide interactions, Curr. Top. Microbiol. Immunol., 362, 111-26 (2012).

Scott, J.L., Musselman, C.A., Adu-Gyamfi, E., Kutateladze, T.G. and Stahelin, R.V. Emerging methodologies to investigate lipid-protein interactions. Integr. Biol. 4, 247-58 (2012).

Doebele, R.C., Pilling, A., Aisner, D.L., Kutateladze, T.G., Le, A., Weickhardt, A., Kondo, K.L., Linderman, D., Heasley, L.E., Franklin, W.A., Varella-Garcia, M. and Camidge, D.R. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin. Cancer Res., 18, 1472-82 (2012).

Avvakumov, N., Lalonde, M.E., Saksouk, N., Paquet, E., Glass, K.C., Landry, A.J., Doyon, Y., Cayrou, C., Robitaille, G., Richard, D., Yang, X.J., Kutateladze T.G. and Côté, J. Conserved molecular interactions within the HBO1 acetyltransferase complexes regulate cell proliferation. Mol. Cell. Biol., 32, 689-703 (2012).

Musselman, C.A., Ramirez, J., Sims, J.K., Mansfield, R.E., Oliver, S.S., Denu, J.M., Mackay, J.P., Wade, P.A., Hagman, J. and Kutateladze, T.G. Bivalent recognition of nucleosomes by the tandem PHD fingers of CHD4 is required for CHD4-mediated repression. Proc. Natl. Acad. Sci. USA, 109, 787-92 (2012).

Oliver, S.S., Musselman, C.A., Hung, H.A., Svaren, J.P., Kutateladze, T.G.  and Denu, J.M. Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry, 51, 6534-44 (2012).

Ali, M., Yan, K., Lalonde, M.E., Degerny, C., Côté, J., Yang, X.J. and Kutateladze, T.G. Tandem PHD fingers of MORF/MOZ acetyltransferases display selectivity for acetylated histone H3 and are required for the association with chromatin, J. Mol. Biol., online Oct 12 (2012).

Musselman, C.A., Avvakumov, N., Watanabe, R., Abraham, C.G., Lalonde, M.E., Hong, Z., Allen, C., Roy, S., Nunez, J., Nickoloff, J., Kulesza, C.A., Yasui, A., Côté, J., and Kutateladze, T.G. Molecular basis for H3K36me3 recognition by the Tudor domain of PHF1, Nature Str. Mol. Biol., 19, online Nov 11 (2012).

Ramirez, J., Dege, C., Kutateladze, T.G.  and Hagman, J. MBD2 and multiple domains of CHD4 are required for transcriptional attenuation by Mi-2/NuRD complexes, Mol. Cell. Biol., online Oct 15 (2012).

Musselman, C.A., Lalonde, M.E., Côté, J. and Kutateladze, T.G. Perceiving the epigenetic landscape through histone readers, Nature Str. Mol. Biol.,19, Dec 5 issue (2012).