Canonical and atypical E2Fs regulate the mammalian endocycle.
The endocycle is a variant cell cycle consisting of successive DNA synthesis and gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals.
Solid Tumor Biology Program, Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Hui-Zi
HZ
Chen
Madhu M
MM
Ouseph
Jing
J
Li
Thierry
T
Pécot
Veda
V
Chokshi
Lindsey
L
Kent
Sooin
S
Bae
Morgan
M
Byrne
Camille
C
Duran
Grant
G
Comstock
Prashant
P
Trikha
Markus
M
Mair
Shantibhusan
S
Senapati
Chelsea K
CK
Martin
Sagar
S
Gandhi
Nicholas
N
Wilson
Bin
B
Liu
Yi-Wen
YW
Huang
John C
JC
Thompson
Sundaresan
S
Raman
Shantanu
S
Singh
Marcelo
M
Leone
Raghu
R
Machiraju
Kun
K
Huang
Xiaokui
X
Mo
Soledad
S
Fernandez
Ilona
I
Kalaszczynska
Debra J
DJ
Wolgemuth
Piotr
P
Sicinski
Tim
T
Huang
Victor
V
Jin
Gustavo
G
Leone
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D050702:E2F7 Transcription Factor; C504722:E2F8 protein, mouse; D012097:Repressor Proteins