E2F8 is essential for polyploidization in mammalian cells

Abstract

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.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…9 These results suggest that E2F8 initiates the endoreplication through repressing the mitosis and cytokinesis.…”

“…Recently, knockout mouse models revealed a remarkable role of E2F transcription factors in regulating cell cycle progress, including mitosis, polyploidization, cell proliferation and apoptosis. [7][8][9] The E2F family of transcription factors consists of 8 members that are synergistically involved in cell cycle regulation. E2F1-3 belong to transcriptional activator and participate in normal cell cycle transitions.…”

“…14,15 Several studies have associated atypical E2Fs in cell proliferation, differentiation and apoptosis, embryo development, angiogenesis, polyploidization of hepatocytes and trophoblast giant cells (TGC) and tumorigenesis. 7,9,[16][17][18][19][20][21][22][23] However, the expression, regulation and function of atypical E2Fs in mouse uterus during early pregnancy are still unknown.…”

“…7,9 Based on our information, this is the first study to focus on the expression of atypical E2Fs in mouse uterus during early pregnancy. E2F7 and E2F8 are negative in mouse uteri from days 1 to 4.…”

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

“…Although the process of liver polyploidization has been documented extensively (6)(7)(8), this phenomenon remains poorly understood. During postnatal development, a scheduled division program characterized by incomplete cytokinesis results in the genesis of binuclear tetraploid hepatocytes (2x2n), which subsequently play a pivotal role in liver polyploidization (3,(9)(10)(11). Remarkably, during postnatal development and adult life, hepatocytes are able to increase their DNA content but also reduce it through a process call "ploidy reversal" (2,12).…”