Publications by authors named "Veda Chokshi"

3 Publications

  • Page 1 of 1

E2f8 mediates tumor suppression in postnatal liver development.

J Clin Invest 2016 08 25;126(8):2955-69. Epub 2016 Jul 25.

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.
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http://dx.doi.org/10.1172/JCI85506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966321PMC
August 2016

Canonical and atypical E2Fs regulate the mammalian endocycle.

Nat Cell Biol 2012 Nov 14;14(11):1192-202. Epub 2012 Oct 14.

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.

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.
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http://dx.doi.org/10.1038/ncb2595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616487PMC
November 2012

Atypical E2F repressors and activators coordinate placental development.

Dev Cell 2012 Apr;22(4):849-62

Solid Tumor Biology Program, Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA.

The evolutionarily ancient arm of the E2f family of transcription factors consisting of the two atypical members E2f7 and E2f8 is essential for murine embryonic development. However, the critical tissues, cellular processes, and molecular pathways regulated by these two factors remain unknown. Using a series of fetal and placental lineage-specific cre mice, we show that E2F7/E2F8 functions in extraembryonic trophoblast lineages are both necessary and sufficient to carry fetuses to term. Expression profiling and biochemical approaches exposed the canonical E2F3a activator as a key family member that antagonizes E2F7/E2F8 functions. Remarkably, the concomitant loss of E2f3a normalized placental gene expression programs, corrected placental defects, and fostered the survival of E2f7/E2f8-deficient embryos to birth. In summary, we identified a placental transcriptional network tightly coordinated by activation and repression through two distinct arms of the E2F family that is essential for extraembryonic cell proliferation, placental development, and fetal viability.
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http://dx.doi.org/10.1016/j.devcel.2012.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483796PMC
April 2012