Polycomb complexes repress developmental regulators in murine embryonic stem cells.
The mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Polycomb group (PcG) proteins are transcriptional repressors that help to maintain cellular identity during metazoan development by epigenetic modification of chromatin structure. PcG proteins have essential roles in early embryonic development and have been implicated in ES cell pluripotency, but few of their target genes are known in mammals. Here we show that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation. Using genome-wide location analysis in murine ES cells, we found that the Polycomb repressive complexes PRC1 and PRC2 co-occupied 512 genes, many of which encode transcription factors with important roles in development. All of the co-occupied genes contained modified nucleosomes (trimethylated Lys 27 on histone H3). Consistent with a causal role in gene silencing in ES cells, PcG target genes were de-repressed in cells deficient for the PRC2 component Eed, and were preferentially activated on induction of differentiation. Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.
Boyer
Laurie A
LA
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Plath
Kathrin
K
Zeitlinger
Julia
J
Brambrink
Tobias
T
Medeiros
Lea A
LA
Lee
Tong Ihn
TI
Levine
Stuart S
SS
Wernig
Marius
M
Tajonar
Adriana
A
Ray
Mridula K
MK
Bell
George W
GW
Otte
Arie P
AP
Vidal
Miguel
M
Gifford
David K
DK
Young
Richard A
RA
Jaenisch
Rudolf
R
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D046912:Multiprotein Complexes; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins