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.
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E2f7 and E2f8 are expressed in several other tissues, such as placenta and pancreas, where they are implicated in arresting the cell cycle.
“These mitotic inhibitors are expressed in several other tissues, such as the placenta and pancreas, where they are also implicated in arresting the cell cycle (8, 47–49).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [8]
In the liver, E2f7 and E2f8 are responsible for cell cycle arrest that uncouples DNA synthesis from proliferation.
“In the liver, two members of the E2F family of cell cycle regulators, E2f7 and E2f8, are responsible for this form of cell cycle arrest (7, 8).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [8]
E2F7 and E2F8 inhibit expression of many genes including Aurka/b, Ccnb1, and Plk1.
“Acting as mutually redundant transcriptional repressors, E2F7 and E2F8 inhibit the expression of many genes, including Aurka/b, Ccnb1, and Plk1, which encode proteins that act during mitotic progression (7, 8, 11).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [8]
Deleting E2f7 and E2f8 from hepatocytes results in completion of M phase and generation of diploid daughter cells.
“Deleting E2f7 and E2f8 from hepatocytes results in completion of M phase and the generation of diploid daughter cells (7, 8).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [8]
E2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.
“E2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.38,70”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [70]
E2F7 and E2F8 are responsible for cell cycle arrest in the liver.
“Two members of the E2F family of cell cycle regulators, E2F7 and E2F8, are responsible for this form of cell cycle arrest in the liver (Chen et al. 2012;Pandit et al. 2012).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Pandit et al. 2012
In the liver, DNA synthesis is uncoupled from cell proliferation due to the activity of E2F7 and E2F8.
“Therefore, in the liver, DNA synthesis is uncoupled from cell proliferation due to the activity of E2F7 and E2F8.”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Pandit et al. 2012
These mitotic inhibitors are expressed in several other tissues besides the liver where they are also implicated in arresting the cell cycle.
“These mitotic inhibitors are expressed in several other tissues besides the liver where they are also implicated in arresting the cell cycle (Matondo et al. 2018;Mizuno et al. 2019;Pandit et al. 2012;Qi et al. 2015).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Pandit et al. 2012
Deleting E2f7 and E2f8 from liver cells results in completion of M phase and generation of diploid daughter cells.
“Deleting E2f7 and E2f8 from these cells results in completion of M phase and the generation of diploid daughter cells (Chen et al. 2012;Pandit et al. 2012).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Pandit et al. 2012
In several tissues including the liver, transcriptional repressors E2F7 and E2F8 function as inhibitors of mitosis and promote polyploidy.
“In several tissues including the liver, transcriptional repressors such as E2F7 and E2F8 function as inhibitors of mitosis and promote polyploidy”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Pandit et al. 2012
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“Acknowledgment: We thank Gustavo Leone (The Ohio State University) and Alain deBruin (Utrecht University) for sharing liver-specific E2f 7/E2f 8 knockout mice.”
InfluentialSmg6/Est1 licenses embryonic stem cell differentiation via nonsense‐mediated mRNA decay
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Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer
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E2F Transcription Factors Control the Roller Coaster Ride of Cell Cycle Gene Expression
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Remote reprogramming of hepatic circadian transcriptome by breast cancer
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“Several studies have found that E2f7 and E2f8 deficiency does not disrupt liver architecture or alter gene expression in mice between weeks 3 and 16.(21,22,25) Moreover, Lu et al(35) found gene expression was similar between diploid and polyploid hepatocytes, suggesting ploidy populations are equivalent at the RNA lev…”
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“Similarly, cytokinesis failure is also observed in bi-nucleated hepatocytes.35 E2F7 and E2F8, 2 atypical members in E2F family, are essential for the polyploidization of hepatocytes and TGC.7,9 Based on our information, this is the first study to focus on the expression of atypical E2Fs in mouse uterus during early pr…”
BackgroundMethodInfluentialCell Cycle Re-entry in the Nervous System: From Polyploidy to Neurodegeneration
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“Consistently, liver-specific loss of either E2F1 or E2F7/E2F8 results in hyper- and hypoploidization, respectively (Chen et al., 2012; Pandit et al., 2012).”
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“In mammalian hepatocytes the E2F7 and E2F8 transcription factors are required for polyploidization, but when they are knocked out hepatocyte differentiation and liver regeneration do not appear to be affected (Pandit et al., 2012).”
BackgroundNehme, Z., Pasquereau, S., Ahmad, S. H., Baba, R. E., & Herbein, G. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104056 · Cited by 48 · see citing works
“85 Interestingly, E2F8, an atypical transcription factor regulated by STAT3 signaling, was shown to be essential for polyploidization in mammalian cells, 86 potentially participating in the induction of > 4N population observed upon infection with the high-risk strains (Figure 1f).”
Multicilin and activated E2f4 induce multiciliated cell differentiation in primary fibroblasts
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E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma
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PIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis
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“…component PIDD1 and the executioner component, caspase-2, is coupled to proliferation, as it is controlled by antagonizing members of the E2F transcription factor family, known for their essential role in ploidy control (Conner et al , 2003; Pandit et al , 2012; Chen et al , 2012).”
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“These results are intriguing considering a proposed role of atypical E2Fs in maintenance of genome size and cancer, but E2F7 and E2F8 function was not further explored in this study(33,34).”
Polyploidy control in hepatic health and disease
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“Moreover, E2f7/E2f8 knockout livers, which are predominantly diploid, did not exhibit a higher liver mass recovery rate after hepatectomy compared to wild-type livers [75].”
BackgroundInfluentialPolyploid cardiomyocytes: implications for heart regeneration
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“We also analyzed the orientation of the mitotic SA relative to the apical PA in hepatocytes in vivo in fixed liver tissue from young healthy mice (Figure S1A) and rats (Figure 2C and 2D), which display a burst of cell division after weaning [26,29].”
Self-citationAtypical E2fs Control Lymphangiogenesis through Transcriptional Regulation of Ccbe1 and Flt4
Weijts, B., van Impel, A., Schulte-Merker, S., & de Bruin, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073693 · Cited by 37 · see citing works
“E2f7/8 function predominantly as transcriptional repressors of cell cycle genes involved in DNA replication, DNA metabolism, DNA repair, mitosis and cytokinesis [9,10].”
E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice
Moreno, E., Toussaint, M. J. M., van Essen, S. C., Bongiovanni, L., van Liere, E. A., Koster, M. H., Yuan, R., van Deursen, J. M., Westendorp, B., & de Bruin, A. (2021) · Hepatology · doi:10.1002/hep.31259 · Cited by 37 · see citing works
“Nuclei suspensions from frozen liver tissue were obtained as described.(36) Details can be found in the Supporting Information.”
MethodSelf-citationRotelli, M. D., Policastro, R. A., Bolling, A. M., Killion, A. W., Weinberg, A. J., Dixon, M. J., Zentner, G. E., Walczak, C., Lilly, M. A., & Calvi, B. R. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008253 · Cited by 37 · see citing works
“Nonetheless, subsequent studies showed that this property is conserved in endoreplicating cells of mouse liver, megakaryocytes, and trophoblast giant cells (Chen et al., 2012; Pandit et al., 2012; Zielke et al., 2011).”
BackgroundFeedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression
Boekhout, M., Yuan, R.-X., Wondergem, A. P., Segeren, H. A., Liere, E. A., Awol, N., Jansen, I., Wolthuis, R., de Bruin, A., & Westendorp, B. (2016) · EMBO Reports · doi:10.15252/embr.201540984 · Cited by 36 · see citing works
“CDC6 and cyclin A2 are prominent examples, but in fact 27% of the genes from a published curated list of APC/C substrates [36,37] are E2F7 and E2F8 target genes we have previously identified [8,10] (Fig 6H).”
Self-citationLiu, B.-Y., Shats, I., Angus, S. P., Gatza, M., & Nevins, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.467506 · Cited by 36 · see citing works
New insights into the dynamics of plant cell nuclei and chromosomes.
Matsunaga, S., Katagiri, Y., Nagashima, Y., Sugiyama, T., Hasegawa, J., Hayashi, K., & Sakamoto, T. (2013) · International Review of Cell and Molecular Biology · doi:10.1016/b978-0-12-407695-2.00006-8 · Cited by 33 · see citing works
Segeren, H. A., van Rijnberk, L. M., Moreno, E., Riemers, F., van Liere, E. V., Yuan, R.-X., Wubbolts, R., de Bruin, A., & Westendorp, B. (2020) · bioRxiv · doi:10.1101/2020.03.19.998674 · Cited by 32 · see citing works
“Liver-specific deletion of E2f7/8 prevented polyploidization and promoted liver tumor growth, further supporting this notion (Chen et al., 2012; Kent et al., 2016; Pandit et al., 2012).”
BackgroundSelf-citationCircadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
Chao, H.-W., Doi, M., Fustin, J., Chen, H.-T., Murase, K., Maeda, Y., Hayashi, H., Tanaka, R., Sugawa, M., Mizukuchi, N., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02207-7 · Cited by 31 · see citing works
Distinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
Sahni, J. M., Gayle, S. S., Webb, B., Weber-Bonk, K. L., Seachrist, D. D., Singh, S., Sizemore, S., Restrepo, N. A., Bebek, G., Scacheri, P., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1571 · Cited by 30 · see citing works
“Of these factors, four (FOXM1, E2F8, LIN9, and MYBL2) are associated with polyploidy (39-42), a key response we observed in TNBC cells following treatment with BETi (12).”
BackgroundTransient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability
Chen, S., Stout, J. R., Dharmaiah, S., Yde, S. E., Calvi, B., & Walczak, C. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-03-0159 · Cited by 30 · see citing works
“Previous studies also showed that a similar group of mitotic genes are down-regulated in Drosophila and mouse endocycling cells (Maqbool et al., 2010; Chen et al., 2012; Pandit et al., 2012).”
ResultKim, S., Jeon, Y., Kim, H.-S., Lee, J.-K., Lim, H.-J., Kang, D.-H., Cho, H., Park, C., Lee, H., & Lee, C.-W. (2016) · Hepatology · doi:10.1002/hep.28281 · Cited by 30 · see citing works
Moreno-Marín, N., Merino, J. M., Álvarez-Barrientos, A., Patel, D. P., Takahashi, S., González-Sancho, J., Gandolfo, P., Rios, R., Muñoz, A., Gonzalez, F., et al. (2018) · iScience · doi:10.1016/j.isci.2018.05.006 · Cited by 29 · see citing works
“Interestingly, lack of E2F8 transcription factor impairs polyploidization in mouse liver through overexpression of E2F-dependent target genes (Pandit et al., 2012), thus producing a phenotype similar to that present in AhR-null mice.”
BackgroundDjabrayan, N. J., Cruz, J., de Miguel, C., Franch-Marro, X., & Casanova, J. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.043 · Cited by 29 · see citing works
“Indeed, inhibition of endoreplication has been reported without gross effect (Chen et al., 2012; Pandit et al., 2012), raising the suggestion that polyploidy could be dispensable in some cases (Meserve and Duronio, 2012).”
BackgroundBach, F., Rutten, K. A., Hendriks, K., Riemers, F., Cornelissen, P. W. A., de Bruin, A., Arkesteijn, G., Wubbolts, R., Horton, W., Penning, L., et al. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24658 · Cited by 29 · see citing works
“The ChIP assay was performed as described previously (Pandit et al., 2012), with minor modifications.”
MethodSelf-citationWound-Induced Polyploidy Is Required for Tissue Repair
Losick, V. P. (2014) · Advances in Wound Care · doi:10.1089/wound.2014.0545 · Cited by 31 · see citing works
“Alternatively, conditional null mutant mice for either e2f7 and/or e2F8 do not develop polyploid hepatocytes yet also regenerate normally by hepatocyte mitotic division.(42,43) Therefore, polyploidy and cell division function appear to be acting redundantly; when one process is impeded the other compensates.”
BackgroundFOUR LIPS and MYB88 conditionally restrict the G1/S transition during stomatal formation
Lee, E., Liu, X.-G., Eglit, Y., & Sack, F. (2013) · Journal of Experimental Botany · doi:10.1093/jxb/ert313 · Cited by 27 · see citing works
“In addition, endomitosis can lead to nuclear division without cytokinesis, resulting in the formation of several nuclei in one cell (Meserve and Duronio, 2012; Pandit et al., 2012).”
BackgroundWnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
“Deleting E2f7 and E2f8 from hepatocytes results in completion of M phase and the generation of diploid daughter cells (7, 8).”
BackgroundIHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice
Li, B., Yan, Y., He, Y., Chen, L., Li, M., Wang, Y., & Yang, Z. (2023) · Science Signaling · doi:10.1126/scisignal.add0645 · Cited by 29 · see citing works
“Expression of two decidualization makers (Prl8a2 and Prl3c1) (43) and E2f8, which encodes an E2F transcription factor that is present in cells that will become polyploid, such as trophoblasts (54, 55), was also significantly promoted by SHH (Fig.”
BackgroundSusceptibility to Plasmodium liver stage infection is altered by hepatocyte polyploidy
Austin, L. S., Kaushansky, A., & Kappe, S. (2014) · Cellular Microbiology · doi:10.1111/cmi.12282 · Cited by 26 · see citing works
“…several cell proliferation proteins, including p53 (Kurinna et al., 2013) and cell cycle transcription factors of the E2F family (Chen et al., 2012; Pandit et al., 2012) have been implicated in the generation of polyploidy in hepatocytes. p53 in particular might be playing a role in the…”
BackgroundEmerging role of E2F8 in human cancer
Lee, D. Y., Chun, J. N., Cho, M., So, I., & Jeon, J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166745 · Cited by 24 · see citing works
Differential roles for diploid and polyploid hepatocytes in acute and chronic liver injury
Wilkinson, P. D., & Duncan, A. (2020) · Seminars in liver disease (Print) · doi:10.1055/s-0040-1719175 · Cited by 25 · see citing works
Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases
Donné, R., Sangouard, F., Celton‐Morizur, S., & Desdouets, C. (2021) · Cancers · doi:10.3390/cancers13205151 · Cited by 28 · see citing works
“studies have suggested that periportal hepatocytes have a smaller polyploid contingent than perivenous hepatocytes [68,69], whereas others have suggested that the proportions of polyploid hepatocytes are similar in these two areas [57,61].”
BackgroundInfluentialCentriole signaling restricts hepatocyte ploidy to maintain liver integrityPreprint
Sladky, V. C., Akbari, H., Tapias-Gomez, D., Evans, L. T., Drown, C. G., Strong, M. A., LoMastro, G. M., Larman, T. C., & Holland, A. (2022) · Genes & Development · doi:10.1101/gad.349727.122 · Cited by 22 · see citing works
“…in both mice and humans (Wilkinson et al. 2018; Sladky et al. 2020a; Heinke et al. 2022), increasing or decreasing hepatocyte ploidy has no impact on basal liver function (Chen et al. 2012; Pandit et al. 2012; Miettinen et al. 2014; Dewhurst et al. 2020; Lin et al. 2020; Sladky et al. 2020b).”
Making big cells: One size does not fit all
Calvi, B. (2013) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1306908110 · Cited by 22 · see citing works
Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers
Matsumoto, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169409 · Cited by 21 · see citing works
“In addition, impairment of hepatocyte polyploidization in E2f7/E2f8 double-knockout mice has no impact on liver differentiation, zonation, or metabolism [26].”
BackgroundInfluentialAmplified centrosomes—more than just a threat
Kiermaier, E., Stötzel, I., Schapfl, M. A., & Villunger, A. (2024) · EMBO Reports · doi:10.1038/s44319-024-00260-0 · Cited by 20 · see citing works
“Of note, ploidy does not seem to affect liver function, nor regenerative proliferation in mice, as documented by comparing mononucleated diploid livers or highly polyploid livers of wild-type animals (Pandit et al, 2012; Zhang et al, 2018; Lin et al, 2020).”
Pek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25 · see citing works
Functional consequences of somatic polyploidy in development
Darmasaputra, G., van Rijnberk, L. M., & Galli, M. (2024) · Development · doi:10.1242/dev.202392 · Cited by 31 · see citing works
“Surprisingly, tissue-specific inhibition of polyploidization in these tissues does not result in gross physiological defects but only impairs tissue functioning under stress conditions (Chen et al., 2012; Matondo et al., 2018; Pandit et al., 2012).”
Patterson, M., & Swift, S. K. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0193 · Cited by 19 · see citing works
“…of a mouse model ( E2f7/E2f8 double knockout) displaying an abnormally high frequency of diploid hepatocytes (70%–80% diploid) failed to reveal heightened liver regenerative capacity or 5-bromo-2’-deoxyuridine (BrdU) incorporation after PHx [69], as the hypothesis posited here would predict.”
E2F/DP prevents cell cycle progression in endocycling fatbody cells by suppressing dATM expression
Guarner, A., Morris, R., Korenjak, M., Boukhali, M., Zappia, M., Rechem, C. V., Whetstine, J., Ramaswamy, S., Zou, L., Frolov, M., et al. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.11.008 · Cited by 19 · see citing works
“Also, both canonical and atypical E2F members regulate endocycles in placental and liver cells through the regulation of cell-cycle and DNA repair genes (Chen et al., 2012; Pandit et al., 2012).”
Atypical E2Fs inhibit tumor angiogenesis
Weijts, B., Westendorp, B., Hien, B., Martínez-López, L., Zijp, M., Thurlings, I., Thomas, R., Schulte-Merker, S., Bakker, W., & de Bruin, A. (2017) · Oncogene · doi:10.1038/onc.2017.336 · Cited by 19 · see citing works
Self-citationWhole-Genome Doubling as a source of cancer: how, when, where, and why?
Sanz‐Gómez, N., González-Álvarez, M., Rivas, J. D. L., & de Cárcer, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1209136 · Cited by 23 · see citing works
“E2F7/8 are transcriptional repressors of genes such as ECT2, RacGAP, and MKLP1, which are essential regulators for successful cytokinesis ((Pandit et al., 2012) and reviewed in (Donne et al.”
BackgroundThe antagonistic relationship between apoptosis and polyploidy in development and cancer
Herriage, H. C., Huang, Y., & Calvi, B. R. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.05.009 · Cited by 23 · see citing works
Luisier, R., Unterberger, E. B., Goodman, J. I., Schwarz, M., Moggs, J. G., Terranova, R., & van Nimwegen, E. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1415 · Cited by 18 · see citing works
“E2F7 and E2F8 have been recently shown to play a key role in positively regulating hepatocyte polyploidy (63,64).”
BackgroundEndomitosis controls tissue-specific gene expression during development
van Rijnberk, L. M., Barrull-Mascaró, R., van der Palen, R. L., Schild, E. S., Korswagen, H., & Galli, M. (2021) · bioRxiv · doi:10.1371/journal.pbio.3001597 · Cited by 16 · see citing works
Cellular polyploidy in organ homeostasis and regeneration
Fang, J.-T., de Bruin, A., Villunger, A., Schiffelers, R., Lei, Z., & Sluijter, J. (2022) · Protein & Cell · doi:10.1093/procel/pwac064 · Cited by 14 · see citing works
“A similar phenomenon was also observed in the E2f7/8-deficienct liver which is composed of predominately diploid hepatocytes, and no significant difference in regenerative capacity was found between the wild-type and E2f7/8-deficienct mice (Pandit et al., 2012).”
Atypical E2f functions are critical for pancreas polyploidization
Matondo, R. B., Moreno, E., Toussaint, M. J. M., Tooten, P. C. J., van Essen, S. C., van Liere, E. A., Youssef, S. A., Bongiovanni, L., & de Bruin, A. (2018) · PLOS ONE · doi:10.1371/journal.pone.0190899 · Cited by 14 · see citing works
“In contrast, loss of activator E2fs results in reduced E2F target expression and enhances polyploidy in the pancreas, liver and placenta [7, 8, 22].”
InfluentialSelf-citationRutten, M., Derks, T., Huijkman, N., Bos, T., Kloosterhuis, N., van de Kolk, K. V. D., Wolters, J., Koster, M. H., Bongiovanni, L., Thomas, R., et al. (2021) · Hepatology · doi:10.1002/hep.32022 · Cited by 13
Moreno, E., Pandit, S. K., Toussaint, M. J. M., Bongiovanni, L., Harkema, L., van Essen, S. C., van Liere, E. A., Westendorp, B., & de Bruin, A. (2021) · Cancers · doi:10.3390/cancers13092033 · Cited by 12 · see citing works
“Previous studies demonstrated that loss of RB enhances liver cell polyploidization, whereas ablation of E2F7/8 prevents polyploidization [34,35].”
BackgroundSelf-citationAtypical E2Fs drive atypical cell cycles
Meserve, J. H., & Duronio, R. J. (2012) · Nature Cell Biology · doi:10.1038/ncb2609 · Cited by 13 · see citing works
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
Darmasaputra, G. S., Geerlings, C. C., Lopes, S. M. C. D. S., Clevers, H., & Galli, M. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202403020 · Cited by 12 · see citing works
“Indeed, knockout of E2F7 and E2F8 in mouse livers led to an increase in expression of M phase genes, and E2F8 has also been shown to bind to promoters of M phase genes in human cells (Pandit et al., 2012).”
BackgroundMethodInfluentialLoss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development
Chu, H.-H. S., Chabon, J. R., Matovina, C., Minehart, J., Chen, B.-R., Zhang, J., Kumar, V., Xiong, Y.-J., Callen, E., Hung, P. J., et al. (2020) · iScience · doi:10.1016/j.isci.2020.100941 · Cited by 12 · see citing works
“Lig4: forward (5'-TCTGCCTTTAAGCCAATGCT-3'), reverse (5'- GTGAGAGAGCCTTCCTGTGG-3'); Xrcc4: forward (5'-TGTGTGAGTGCCAAAGAAGC3'), reverse (5'-TCATCGGTGCTTCCATCATA-3') (Okamura et al., 2016); Lig3: forward (5'-CCTCTCCAAGCTCACCAAAG-3'), reverse (5'-TGCTCATTGTGAAGGACTCG-3'); Parp1: forward (5'-GCAGCGAGAGTATTCCCAAG-3'), reve…”
The Spectrum of E2F in Liver Disease-Mediated Regulation in Biology and Cancer
Huntington, J. T., Tang, X., Kent, L. N., Schmidt, C. R., & Leone, G. W. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.25242 · Cited by 12 · see citing works
“Despite the increased polyploidy that is thought to be important for liver regeneration, E2F7/8 deficient mouse livers with significantly reduced polyploidy are able to regenerate as well as wild-type livers (Chen et al., 2012;Meserve andDuronio, 2012; Pandit et al., 2012).”
BackgroundThe Ploidy State as a Determinant of Hepatocyte Proliferation
Wilson, S. R., & Duncan, A. W. (2023) · Seminars in liver disease (Print) · doi:10.1055/a-2211-2144 · Cited by 11 · see citing works
“24,29 Similarly, the expression of PIDDosome complex members, Pidd1 and Casp2 , is negatively regulated by E2F7 and E2F8.”
BackgroundMethod
- Authors
- Pandit, S. K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C. J., Cornelissen, P. W. A., Toussaint, M. J. M., Lamers, W. H., & de Bruin, A.
- Affiliations
- Utrecht University (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Nature Cell Biology
- Published
- 2012-10-14
- Volume
- 14
- Issue
- 11
- Pages
- 1181-1191
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2164721923
- Cited by
- 168
- References
- 0
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 8 · 2023: 12 · 2022: 13 · 2021: 11 · 2020: 18 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 10 · 2015: 13 · 2014: 13 · 2013: 14 · 2012: 2
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Roche Nederland
- Universiteit Utrecht
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- E2F8, E2F1, polyploidization, hepatocytes, incomplete cytokinesis, binucleation, transcriptional repression, E2F target genes, liver regeneration, liver differentiation, liver zonation, cellular senescence, weaning
- MeSH terms
- Animals, Cell Differentiation, Humans, Liver, Polyploidy, Repressor Proteins, Mice, Knockout, Hepatocytes, E2F1 Transcription Factor, E2F7 Transcription Factor, Mice, Hep G2 Cells
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