A chemical biology toolbox to study protein methyltransferases and epigenetic signaling

Sebastian Scheer, Suzanne Ackloo, Tiago S. Medina, Matthieu Schapira, Fengling Li, Jennifer A. Ward, Andrew M. Lewis, Jeffrey P. Northrop, Paul L. Richardson, H. Ümit Kaniskan, Yudao Shen, Jing Liu, David Smil, David McLeod, Carlos A. Zepeda-Velazquez, Minkui Luo, Jian Jin, Dalia Barsyte-Lovejoy, Kilian V. M. Huber, Daniel D. Carvalho, Masoud Vedadi, Colby Zaph (), Peter J. Brown () and Cheryl H. Arrowsmith ()
Additional contact information
Sebastian Scheer: Monash University
Suzanne Ackloo: University of Toronto
Tiago S. Medina: University Health Network
Matthieu Schapira: University of Toronto
Fengling Li: University of Toronto
Jennifer A. Ward: University of Oxford
Andrew M. Lewis: University of Oxford
Jeffrey P. Northrop: Monash University
Paul L. Richardson: AbbVie Inc., 1 North Waukegan Rd
H. Ümit Kaniskan: Icahn School of Medicine at Mount Sinai
Yudao Shen: Icahn School of Medicine at Mount Sinai
Jing Liu: Icahn School of Medicine at Mount Sinai
David Smil: University of Toronto
David McLeod: Ontario Institute for Cancer Research
Carlos A. Zepeda-Velazquez: Ontario Institute for Cancer Research
Minkui Luo: Memorial Sloan Kettering Cancer Center
Jian Jin: Icahn School of Medicine at Mount Sinai
Dalia Barsyte-Lovejoy: University of Toronto
Kilian V. M. Huber: University of Oxford
Daniel D. Carvalho: University Health Network
Masoud Vedadi: University of Toronto
Colby Zaph: Monash University
Peter J. Brown: University of Toronto
Cheryl H. Arrowsmith: University of Toronto

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07905-4

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DOI: 10.1038/s41467-018-07905-4

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