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Nat Commun. 2019 Jan 3;10(1):19. doi: 10.1038/s41467-018-07905-4.

A chemical biology toolbox to study protein methyltransferases and epigenetic signaling.

Author information

1
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
2
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
3
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
4
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
5
Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
6
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
7
AbbVie Inc., 1 North Waukegan Rd, North Chicago, IL, 60064, USA.
8
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
9
Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
10
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
11
Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, 10021, USA.
12
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
13
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia. colby.zaph@monash.edu.
14
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. peterj.brown@utoronto.ca.
15
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. cheryl.arrowsmith@uhnresearch.ca.
16
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada. cheryl.arrowsmith@uhnresearch.ca.
17
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada. cheryl.arrowsmith@uhnresearch.ca.

Abstract

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4+ T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.

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