Journal
NATURE CHEMICAL BIOLOGY
Volume 7, Issue 8, Pages 566-574Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.599
Keywords
-
Categories
Funding
- National Institute of General Medical Sciences
- US National Institutes of Health (NIH) [RC1GM090732]
- University of North Carolina at Chapel Hill
- US National Science Foundation (NSF)
- Ontario Research Fund
- Ontario Ministry of Health and Long-term Care
- Structural Genomics Consortium
- Canadian Institutes for Health Research (CIHR) [199170, 186007, IG1-102956]
- Canada Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co. Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- NIH [MH074127, MH088413, DP3DK085698, HG004535]
- NSF [CBET-0941143]
- American Society for Mass Spectrometry
- NIH Office of the Director [DP2OD007447]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0955485] Funding Source: National Science Foundation
Ask authors/readers for more resources
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available