title: E2f8 mediates tumor suppression in postnatal liver development.
abstract: E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Kent
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Rakijas
authors.forename: Shusil K
authors.initials: SK
authors.lastname: Pandit
authors.forename: Bart
authors.initials: B
authors.lastname: Westendorp
authors.forename: Hui-Zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Justin T
authors.initials: JT
authors.lastname: Huntington
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.forename: Sooin
authors.initials: S
authors.lastname: Bae
authors.forename: Arunima
authors.initials: A
authors.lastname: Srivastava
authors.forename: Shantibhusan
authors.initials: S
authors.lastname: Senapati
authors.forename: Christopher
authors.initials: C
authors.lastname: Koivisto
authors.forename: Chelsea K
authors.initials: CK
authors.lastname: Martin
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cuitino
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez
authors.forename: Julian M
authors.initials: JM
authors.lastname: Clouse
authors.forename: Veda
authors.initials: V
authors.lastname: Chokshi
authors.forename: Neelam
authors.initials: N
authors.lastname: Shinde
authors.forename: Raleigh
authors.initials: R
authors.lastname: Kladney
authors.forename: Daokun
authors.initials: D
authors.lastname: Sun
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez-Castro
authors.forename: Ramadhan B
authors.initials: RB
authors.lastname: Matondo
authors.forename: Sathidpak
authors.initials: S
authors.lastname: Nantasanti
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Raghu
authors.initials: R
authors.lastname: Machiraju
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Kamal S
authors.initials: KS
authors.lastname: Pohar
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.forename: Carl R
authors.initials: CR
authors.lastname: Schmidt
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000483:Alleles; D000818:Animals; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D004247:DNA / Q000032:analysis; D050702:E2F7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D000072417:Protein Domains; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
chemical_list: D050702:E2F7 Transcription Factor; C481054:E2F7 protein, human; C504723:E2F8 protein, human; C504722:E2F8 protein, mouse; C479901:E2f7 protein, mouse; D012097:Repressor Proteins; D004247:DNA