Dr. Dalia Barsyte-Lovejoy, PhD is an Assistant Professor at the Department of Pharmacology and Toxicology, UofT, and Principal Investigator at the SGC-Toronto, working to understand fundamental regulatory mechanisms of epigenetic proteins and their pharmacological modulation in cancer. The group’s research focuses on disease mechanisms, therapeutic targets, and chemical probe discovery, resulting in over 30 extensively characterized compounds that have helped shape the emerging field of epigenetics and enabled over 50 collaborative projects that are uncovering new epigenetic mechanisms in cancer and its treatment.
We are interested in understanding the mechanism of epigenetic regulators and posttranslational modifications that control cancer cell growth, differentiation, and therapy response. Protein lysine and arginine methyltransferases regulate transcription, genome stability, splicing, RNA metabolism, and other cell processes dictated by which substrates these enzymes methylate. Lysine methyltransferases such as EZH2 and NSD2 primarily methylate histones to establish repressive and active chromatin. In contrast, arginine methyltransferases have a broad scope of substrates ranging from histones to signaling molecules, enzymes, and structural proteins. Epigenetic chromatin regulation, transcriptome, and cellular signaling are fine-tuned by ubiquitin modification. Our work seeks to understand how these posttranslational modifications are misregulated in cancer and identify new therapeutic targets.
Through multidisciplinary research that includes cell and chemical biology, protein structural biology, and many collaborative studies with colleagues across industry and academia, the SGC chemical probes project has generated several probes for methyltransferases, ubiquitin ligases, and deubiquitylases. We are currently using these chemical probes to explore the cellular pathways in poor prognosis acute myeloid leukemia, pancreatic, lung and breast cancer.
Epigenetics and chromatin architecture regulators
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Epigenetics is about how the DNA code is regulated. Proteins that bind/modify DNA and histones play essential roles in cell identity determination, transcription, and genome maintenance. They are often responsible for diseases such as cancer or uncontrolled inflammation. We are studying how epigenetic proteins regulate normal cell processes and how these are subverted in disease. |
Chemical probes as tools for cancer target discovery
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To study epigenetic modifier proteins, we need genetic and pharmacological tools. Chemical probe compounds that potently and selectively inhibit or degrade the target proteins in cells provide tools for modulating activating/repressing histone marks and other cellular signaling pathways. By discovering and using chemical probes, we expand our understanding of the protein function and its therapeutic utility to establish a biological rationale in cancer therapy.
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Link to Open Lab notebooks that features science community posts on our various projects https://openlabnotebooks.org/
Barsyte-Lovejoy D, Szewczyk MM, Prinos P, Lima-Fernandes E, Ackloo S, Arrowsmith CH
Meth. Enzymol.. 2016-2-16 . 574:79-103 .doi: 10.1016/bs.mie.2016.01.011
PMID: 27423858Ferreira de Freitas R, Eram MS, Szewczyk MM, Steuber H, Smil D, Wu H, Li F, Senisterra G, Dong A, Brown PJ, Hitchcock M, Moosmayer D, Stegmann CM, Egner U, Arrowsmith C, Barsyte-Lovejoy D, Vedadi M, Schapira M
J. Med. Chem.. 2016-1-29 . .doi: 10.1021/acs.jmedchem.5b01772
PMID: 26824386Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, Dirks PB
Cancer Cell. 2015-11-25 . .doi: 10.1016/j.ccell.2015.10.005
PMID: 26626085Eram MS, Shen Y, Szewczyk M, Wu H, Senisterra G, Li F, Butler KV, Kaniskan HÜ, Speed BA, Dela Seña C, Dong A, Zeng H, Schapira M, Brown PJ, Arrowsmith CH, Barsyte-Lovejoy D, Liu J, Vedadi M, Jin J
ACS Chem. Biol.. 2015-11-24 . .doi: 10.1021/acschembio.5b00839
PMID: 26598975Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL
Nature. 2015-9-10 . 525(7568):206-11 .doi: 10.1038/nature15251
PMID: 26331536Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S, Kuznetsova E, Smil D, Barsyte-Lovejoy D, Li F, Poda G, Schapira M, Wu H, Dong A, Senisterra G, Stukalov A, Huber KV, Schönegger A, Marcellus R, Bilban M, Bock C, Brown PJ, Zuber J, Bennett KL, Al-Awar R, Delwel R, Nerlov C, Arrowsmith CH, Superti-Furga G
Nat. Chem. Biol.. 2015-7-13 . .doi: 10.1038/nchembio.1859
PMID: 26167872Smil D, Eram MS, Li F, Kennedy S, Szewczyk MM, Brown PJ, Barsyte-Lovejoy D, Arrowsmith CH, Vedadi M, Schapira M
ACS Med Chem Lett. 2015-4-9 . 6(4):408-12 .doi: 10.1021/ml500467h
PMID: 25893041Nguyen H, Allali-Hassani A, Antonysamy S, Chang S, Chen LH, Curtis C, Emtage S, Fan L, Gheyi T, Li F, Liu S, Martin JR, Mendel D, Olsen JB, Pelletier L, Shatseva T, Wu S, Zhang FF, Arrowsmith CH, Brown PJ, Campbell RM, Garcia BA, Barsyte-Lovejoy D, Mader M, Vedadi M
J. Biol. Chem.. 2015-3-30 . .doi: 10.1074/jbc.M114.626861
PMID: 25825497Kaniskan HÜ, Szewczyk MM, Yu Z, Eram MS, Yang X, Schmidt K, Luo X, Dai M, He F, Zang I, Lin Y, Kennedy S, Li F, Dobrovetsky E, Dong A, Smil D, Min SJ, Landon M, Lin-Jones J, Huang XP, Roth BL, Schapira M, Atadja P, Barsyte-Lovejoy D, Arrowsmith CH, Brown PJ, Zhao K, Jin J, Vedadi M
Angew. Chem. Int. Ed. Engl.. 2015-2-27 . .doi: 10.1002/anie.201412154
PMID: 25728001Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH
Proc. Natl. Acad. Sci. U.S.A.. 2014-8-18 . .doi: 10.1073/pnas.1407358111
PMID: 25136132