H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic geneBCL2determines ERα ligand dependency
Open Access
- 12 August 2011
- journal article
- research article
- Published by Wiley in The EMBO Journal
- Vol. 30 (19), 3947-3961
- https://doi.org/10.1038/emboj.2011.284
Abstract
Chromatin represents a repressive barrier to the process of ligand‐dependent transcriptional activity of nuclear receptors. Here, we show that H3K27 methylation imposes ligand‐dependent regulation of the oestrogen receptor α (ERα)‐dependent apoptotic response via Bcl‐2 in breast cancer cells. The activation of BCL2 transcription is dependent on the simultaneous inactivation of the H3K27 methyltransferase, EZH2, and the demethylation of H3K27 at a poised enhancer by the ERα‐dependent recruitment of JMJD3 in hormone‐dependent breast cancer cells. We also provide evidence that this pathway is modified in cells resistant to anti‐oestrogen (AE), which constitutively express BCL2 . We show that the lack of H3K27 methylation at BCL2 regulatory elements due to the inactivation of EZH2 by the HER2 pathway leads to this constitutive activation of BCL2 in these AE‐resistant cells. Our results describe a mechanism in which the epigenetic state of chromatin affects ligand dependency during ERα‐regulated gene expression.Keywords
This publication has 87 references indexed in Scilit:
- H2AZ Is Enriched at Polycomb Complex Target Genes in ES Cells and Is Necessary for Lineage CommitmentCell, 2008
- Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancersMolecular Carcinogenesis, 2008
- Pathways to tamoxifen resistanceCancer Letters, 2007
- The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene SilencingCell, 2007
- Chromatin Modifications and Their FunctionCell, 2007
- A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem CellsCell, 2006
- The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3Current Opinion in Genetics & Development, 2004
- Histone Methyltransferase Activity of a Drosophila Polycomb Group Repressor ComplexCell, 2002
- Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity that Marks Chromosomal Polycomb SitesCell, 2002
- Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated TranscriptionCell, 2000