A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells.
The Rb/E2F complex represses S-phase genes both in cycling cells and in cells that have permanently exited from the cell cycle and entered a terminal differentiation pathway. Here we show that S-phase gene repression, which involves histone-modifying enzymes, occurs through distinct mechanisms in these two situations. We used chromatin immunoprecipitation to show that methylation of histone H3 lysine 9 (H3K9) occurs at several Rb/E2F target promoters in differentiating cells but not in cycling cells. Furthermore, phenotypic knock-down experiments using siRNAs showed that the histone methyltransferase Suv39h is required for histone H3K9 methylation and subsequent repression of S-phase gene promoters in differentiating cells, but not in cycling cells. These results indicate that the E2F target gene permanent silencing mechanism that is triggered upon terminal differentiation is distinct from the transient repression mechanism in cycling cells. Finally, Suv39h-depleted myoblasts were unable to express early or late muscle differentiation markers. Thus, appropriately timed H3K9 methylation by Suv39h seems to be part of the control switch for exiting the cell cycle and entering differentiation.
Ait-Si-Ali
Slimane
S
UPR 9079 CNRS-Labellisée Ligue Nationale Contre le Cancer, Institut André Lwoff, Villejuif, France.
Guasconi
Valentina
V
Fritsch
Lauriane
L
Yahi
Hakima
H
Sekhri
Redha
R
Naguibneva
Irina
I
Robin
Philippe
P
Cabon
Florence
F
Polesskaya
Anna
A
Harel-Bellan
Annick
A
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D020868:Gene Silencing / Q000502:physiology*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000502:physiology; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases