Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-07905-4
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Funding
- National Institute of Mental Health's (NIMH) Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]
- Canadian Institutes of Health Research [FDN-154328, 128090, FDN-148430, 201512MSH-360794-228629]
- Canadian Cancer Society [CCSRI 703716]
- Australian National Health and Medical Research Council [1104433, 1104466]
- Myeloma UK
- U.S. National Institutes of Health [R01GM122749, R01CA218600, R01HD088626]
- OICR Drug Discovery Program - government of Ontario
- Structural Genomics Consortium (SGC) [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [115766]
- Janssen
- Merck KGaA, Darmstadt, Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Research, Innovation and Science (MRIS)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil
- National Health and Medical Research Council of Australia [1104433, 1104466] Funding Source: NHMRC
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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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