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Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase.
- Source :
-
Molecular cell [Mol Cell] 2007 Feb 09; Vol. 25 (3), pp. 473-81. - Publication Year :
- 2007
-
Abstract
- Histone lysine methylation has important roles in the organization of chromatin domains and the regulation of gene expression. To analyze its function and modulate its activity, we screened for specific inhibitors against histone lysine methyltransferases (HMTases) using recombinant G9a as the target enzyme. From a chemical library comprising 125,000 preselected compounds, seven hits were identified. Of those, one inhibitor, BIX-01294 (diazepin-quinazolin-amine derivative), does not compete with the cofactor S-adenosyl-methionine, and selectively impairs the G9a HMTase and the generation of H3K9me2 in vitro. In cellular assays, transient incubation of several cell lines with BIX-01294 lowers bulk H3K9me2 levels that are restored upon removal of the inhibitor. Importantly, chromatin immunoprecipitation at several G9a target genes demonstrates reversible reduction of promoter-proximal H3K9me2 in inhibitor-treated mouse ES cells and fibroblasts. Our data identify a biologically active HMTase inhibitor that allows for the transient modulation of H3K9me2 marks in mammalian chromatin.
- Subjects :
- Animals
Cell Line
Histone Methyltransferases
Histone-Lysine N-Methyltransferase metabolism
Histone-Lysine N-Methyltransferase physiology
Histones drug effects
Humans
Lysine chemistry
Lysine metabolism
Methylation
Mice
Promoter Regions, Genetic
Protein Methyltransferases
Azepines pharmacology
Enzyme Inhibitors pharmacology
Histone-Lysine N-Methyltransferase antagonists & inhibitors
Histones metabolism
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-2765
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 17289593
- Full Text :
- https://doi.org/10.1016/j.molcel.2007.01.017