PRC2 directly methylates GATA4 and represses its transcriptional activity.
Polycomb-repressive complex 2 (PRC2) promotes tissue-specific differentiation by depositing trimethylated histone H3 Lys 27 (H3K27me3) epigenetic marks to silence ectopic gene expression programs. Here, we show that EZH2, the catalytic subunit of PRC2, is required for cardiac morphogenesis. Both in vitro and in fetal hearts, EZH2 interacted with cardiac transcription factor GATA4 and directly methylated it at Lys 299. PRC2 methylation of GATA4 attenuated its transcriptional activity by reducing its interaction with and acetylation by p300. Our results reveal a new mechanism of PRC2-mediated transcriptional repression in which PRC2 methylates a transcription factor to inhibit its transcriptional activity.
Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Aibin
A
He
Xiaohua
X
Shen
Qing
Q
Ma
Jingjing
J
Cao
Alexander
A
von Gise
Pingzhu
P
Zhou
Gang
G
Wang
Victor E
VE
Marquez
Stuart H
SH
Orkin
William T
WT
Pu
D000818:Animals; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D008745:Methylation; D051379:Mice; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse