E2F8 is essential for polyploidization in mammalian cells.
Polyploidization is observed in all mammalian species and is a characteristic feature of hepatocytes, but its molecular mechanism and biological significance are unknown. Hepatocyte polyploidization in rodents occurs through incomplete cytokinesis, starts after weaning and increases with age. Here, we show in mice that atypical E2F8 is induced after weaning and required for hepatocyte binucleation and polyploidization. A deficiency in E2f8 led to an increase in the expression level of E2F target genes promoting cytokinesis and thereby preventing polyploidization. In contrast, loss of E2f1 enhanced polyploidization and suppressed the polyploidization defect of hepatocytes deficient for atypical E2Fs. In addition, E2F8 and E2F1 were found on the same subset of target promoters. Contrary to the long-standing hypothesis that polyploidization indicates terminal differentiation and senescence, we show that prevention of polyploidization through inactivation of atypical E2Fs has, surprisingly, no impact on liver differentiation, zonation, metabolism and regeneration. Together, these results identify E2F8 as a repressor and E2F1 as an activator of a transcriptional network controlling polyploidization in mammalian cells.
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, The Netherlands.
Shusil K
SK
Pandit
Bart
B
Westendorp
Sathidpak
S
Nantasanti
Elsbeth
E
van Liere
Peter C J
PC
Tooten
Peter W A
PW
Cornelissen
Mathilda J M
MJ
Toussaint
Wouter H
WH
Lamers
Alain
A
de Bruin
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011123:Polyploidy; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D050687:E2F1 Transcription Factor; D050702:E2F7 Transcription Factor; C504722:E2F8 protein, mouse; C493754:E2f1 protein, mouse; C479901:E2f7 protein, mouse; D012097:Repressor Proteins