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. De Carvalho & 4 others Masoud Vedadi, Colby Zaph, Peter J. Brown, Cheryl H. Arrowsmith

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number19
Number of pages14
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 3 Jan 2019

Keywords

  • chemical tools
  • histone post-translational modifications
  • methylation

Cite this

Scheer, S., Ackloo, S., Medina, T. S., Schapira, M., Li, F., Ward, J. A., ... Arrowsmith, C. H. (2019). A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. Nature Communications, 10(1), [19]. https://doi.org/10.1038/s41467-018-07905-4
Scheer, Sebastian ; Ackloo, Suzanne ; Medina, Tiago S. ; Schapira, Matthieu ; Li, Fengling ; Ward, Jennifer A. ; Lewis, Andrew M. ; Northrop, Jeffrey P. ; Richardson, Paul L. ; Kaniskan, H. Ümit ; Shen, Yudao ; Liu, Jing ; Smil, David ; McLeod, David ; Zepeda-Velazquez, Carlos A. ; Luo, Minkui ; Jin, Jian ; Barsyte-Lovejoy, Dalia ; Huber, Kilian V.M. ; De Carvalho, Daniel D. ; Vedadi, Masoud ; Zaph, Colby ; Brown, Peter J. ; Arrowsmith, Cheryl H. / A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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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Scheer, S, Ackloo, S, Medina, TS, Schapira, M, Li, F, Ward, JA, Lewis, AM, Northrop, JP, Richardson, PL, Kaniskan, HÜ, Shen, Y, Liu, J, Smil, D, McLeod, D, Zepeda-Velazquez, CA, Luo, M, Jin, J, Barsyte-Lovejoy, D, Huber, KVM, De Carvalho, DD, Vedadi, M, Zaph, C, Brown, PJ & Arrowsmith, CH 2019, 'A chemical biology toolbox to study protein methyltransferases and epigenetic signaling' Nature Communications, vol. 10, no. 1, 19. https://doi.org/10.1038/s41467-018-07905-4

A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. / Scheer, Sebastian; Ackloo, Suzanne; Medina, Tiago S.; Schapira, Matthieu; Li, Fengling; Ward, Jennifer A.; Lewis, Andrew M.; Northrop, Jeffrey P.; Richardson, Paul L.; Kaniskan, H. Ümit; Shen, Yudao; Liu, Jing; Smil, David; McLeod, David; Zepeda-Velazquez, Carlos A.; Luo, Minkui; Jin, Jian; Barsyte-Lovejoy, Dalia; Huber, Kilian V.M.; De Carvalho, Daniel D.; Vedadi, Masoud; Zaph, Colby; Brown, Peter J.; Arrowsmith, Cheryl H.

In: Nature Communications, Vol. 10, No. 1, 19, 03.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Scheer, Sebastian

AU - Ackloo, Suzanne

AU - Medina, Tiago S.

AU - Schapira, Matthieu

AU - Li, Fengling

AU - Ward, Jennifer A.

AU - Lewis, Andrew M.

AU - Northrop, Jeffrey P.

AU - Richardson, Paul L.

AU - Kaniskan, H. Ümit

AU - Shen, Yudao

AU - Liu, Jing

AU - Smil, David

AU - McLeod, David

AU - Zepeda-Velazquez, Carlos A.

AU - Luo, Minkui

AU - Jin, Jian

AU - Barsyte-Lovejoy, Dalia

AU - Huber, Kilian V.M.

AU - De Carvalho, Daniel D.

AU - Vedadi, Masoud

AU - Zaph, Colby

AU - Brown, Peter J.

AU - Arrowsmith, Cheryl H.

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N2 - 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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