Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Bone marrow transcriptomal differences between wild type, Fancc-deficient, Fancg-deficient, and doubly deficient (Fancc/Fancg) mice.

ABSTRACT: Seeking to challenge the current dogma that the nuclear core-complex proteins function in an entirely epistatic manner, Dr. Clapp's group developed a new double-knockout mouse nullizygous for Fancc and Fancg. Because the hematopoietic phenotype was more severe than single knockout mice, we reasoned that transcriptomal differences would exist and lead to the identification of molecular defects unique to each FA gene. RNA was purified from unfractionated and uncultured bone marrow cells from three types of Fanconi anemia gene knockout mice: nullizygous for Fancc, Fancg, or both Fancc and Fancg.. Three wild type C57Bl/6 mice served as controls. Each of three marrow samples provided one RNA sample (the RNA samples were not pooled).

ORGANISM(S): Mus musculus

SUBMITTER: D Clapp

PROVIDER: E-GEOD-22094 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.

Pulliam-Leath Anna C AC Ciccone Samantha L SL Nalepa Grzegorz G Li Xiaxin X Si Yue Y Miravalle Leticia L Smith Danielle D Yuan Jin J Li Jingling J Anur Praveen P Orazi Attilio A Vance Gail H GH Yang Feng-Chun FC Hanenberg Helmut H Bagby Grover C GC Clapp D Wade DW

Blood 20100706 16

Fanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc(-/-);Fancg(-/-) mice develop spontaneous hematologic seq ...[more]

PMID: 20606166

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Project description:Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure and increased susceptibility to cancer. Of the fifteen FA proteins, Fanconi anemia group C (FANCC) is one of eight FA core complex components of the FA pathway. Unlike other FA core complex proteins, FANCC is mainly localized in the cytoplasm, where it is thought to function in apoptosis, redox regulation, cytokine signaling and other processes. Previously, we showed that regulation of FANCC involved proteolytic processing during apoptosis. To elucidate the biological significance of this proteolytic modification, we searched for molecular interacting partners of proteolytic FANCC fragments. Among the candidates obtained, the transcriptional corepressor protein C-terminal binding protein-1 (CtBP1) interacted directly with FANCC and other FA core complex proteins. Although not required for stability of the FA core complex or ubiquitin ligase activity, CtBP1 is essential for proliferation, cell survival and maintenance of chromosomal integrity. Expression profiling of CtBP1-depleted and FA-depleted cells revealed that several genes were commonly up- and down-regulated, including the Wnt antagonist Dickkopf-1 (DKK1). These findings suggest that FA and Wnt signaling via CtBP1 could share common effectors. HeLa cell line was grown in DMEM media supplemented with 10% FBS and were incubated in 5% CO2 at 37Â°C. A four-plasmid (pRSV-Rev, pMDLg/pRRE, pMD2.G and pLKO.1) expression system was used for lentiviral production. Different pLKO.1 plasmids carrying shRNAs targeting FANCA, FANCD2, CtBP1 or CtBP2 or a lentiviral control vector pLKO.1-scrambled were used. Lentiviral particles were produced via calcium phosphate-mediated transient transfection of the four plasmids into HEK293T cells. Cells were exposed to appropriate lentiviral particles. In each experiment, HeLa cells were transduced for 6 hours with filtered supernatant containing recombinant lentiviral particles. After transduction, the cells were cultured for 72 hours. Total RNA extracts from 3 different samples of each scrambled, CtBPs and FANCD2 shRNA treated HeLa cells were subjected to gene expression profiling via microarray analysis. Gene expression profiles were determined with Affymetrix GeneChipÂ® Human Gene 1.0.

Project description:Zaire ebolavirus (ZEBOV) infections are associated with high lethality in primates. ZEBOV primarily targets mononuclear phagocytes, which are activated upon infection and secrete mediators believed to trigger initial stages of pathogenesis. The characterization of the responses of target cells to ZEBOV infection may therefore not only further understanding of pathogenesis but also suggest possible points of therapeutic intervention. Gene expression profiles of primary human macrophages exposed to ZEBOV were determined using DNA microarrays and quantitative PCR to gain insight into the cellular response immediately after cell entry. Significant changes in mRNA concentrations encoding for 88 cellular proteins were observed. Most of these proteins have not yet been implicated in ZEBOV infection. Some, however, are inflammatory mediators known to be elevated during the acute phase of disease in the blood of ZEBOV-infected humans. Interestingly, the cellular response occurred within the first hour of Ebola virion exposure, i.e. prior to virus gene expression. This observation supports the hypothesis that virion binding or entry mediated by the spike glycoprotein (GP1,2) is the primary stimulus for an initial response. Indeed, ZEBOV virions, LPS, and virus-like particles consisting of only the ZEBOV matrix protein VP40 and GP1,2 (VLPVP40-GP) triggered comparable responses in macrophages, including pro-inflammatory and pro-apoptotic signals. In contrast, VLPVP40 (particles lacking GP1,2) caused an aberrant response. Notably, some cellular interferon-inducible genes were upregulated six hours after exposure to virions and LPS, but not after exposure to VLPVP40-GP. This suggests that GP1,2 binding to macrophages plays an important role in the immediate cellular response. Primary human macrophages from three donors (D1, D2, D3) were harvested at 1 h and 6 h after in vitro exposure to purified Ebola virions and compared to RNA from mock-exposed cells derived from the same donors.

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Dataset Information

Bone marrow transcriptomal differences between wild type, Fancc-deficient, Fancg-deficient, and doubly deficient (Fancc/Fancg) mice.

Publications

Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia.

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