Abstract 10839: Polycomb Repressive Complex 2 Methylates the Transcription Factor GATA4 and Regulates Heart Development
Polycomb Repressive Complex 2, the methyltransferase that establishes repressive trimethylation marks on histone H3 lysine 27 (H3K27me3), promotes tissue-specific differentiation by silencing ectopic gene expression programs. The mechanisms underlying tissue-specific PRC2 repressive activity are incompletely understood, and the role of PRC2 in heart development is unknown. We studied the function of EZH2, encoding the catalytic subunit of PRC2, in murine heart development. EZH2 inactivation early in heart development caused lethal congenital heart malformations. To better understand how EZH2 impacts heart development, we performed RNA-seq and ChIP-seq and identified genes directly repressed by PRC2 deposition of H3K27me3 marks. These were enriched for transcriptional regulators of non-cardiac expression programs, such as transcription factors that regulate neuronal (Pax6) and cardiac progenitor genes (Isl1 and Six1). Spatiotemporal regulation of cardiac gene expression was also disrupted, with Hcn4, Mlc2c, Bmp10, and Myh6 inappropriately upregulated in heart ventricle. Interestingly, EZH2 regulation of these cardiac genes was not dependent upon EZH2 or H3K27me3 occupancy of their promoters. Further investigation identified a novel mechanism of EZH2 repression, in which EZH2 bound and methylated GATA4, a cardiac transcription factor that directly activates cardiac genes such as Myh6. EZH2 methylation of GATA4 reduced its transcriptional activity by blocking its p300 mediated acetylation, a modification that potentiates GATA4 transcriptional activity. In conclusion, our results show that normal establishment of the epigenetic landscape by PRC2 is required for heart development. Furthermore, we discovered a novel mechanism of PRC2 transcriptional repression, in which PRC2 methylates a transcription factor to attenuate its transcriptional activity.
- Cardiac development
- Gene expression
- Molecular biology
- Muscle, cardiac - see Myocardium
- Ventricular septal defect
- © 2011 by American Heart Association, Inc.