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1.
Adv Bioinformatics ; 2012: 876976, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23008709

RESUMO

Reliable identification of copy number aberrations (CNA) from comparative genomic hybridization data would be improved by the availability of a generalised method for processing large datasets. To this end, we developed swatCGH, a data analysis framework and region detection heuristic for computational grids. swatCGH analyses sequentially displaced (sliding) windows of neighbouring probes and applies adaptive thresholds of varying stringency to identify the 10% of each chromosome that contains the most frequently occurring CNAs. We used the method to analyse a published dataset, comparing data preprocessed using four different DNA segmentation algorithms, and two methods for prioritising the detected CNAs. The consolidated list of the most commonly detected aberrations confirmed the value of swatCGH as a simplified high-throughput method for identifying biologically significant CNA regions of interest.

2.
Cell Cycle ; 11(5): 846-55, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22333576

RESUMO

The first differentiation event in mammalian development gives rise to the blastocyst, consisting of two cell lineages that have also segregated in how the cell cycle is structured. Pluripotent cells of the inner cell mass divide mitotically to retain a diploid DNA content, but the outer trophoblast cells can amplify their genomes more than 500-fold by undergoing multiple rounds of DNA replication, completely bypassing mitosis. Central to this striking divergence in cell cycle control is the E3 ubiquitin-ligase activity of the anaphase-promoting complex or cyclosome (APC/C). Extended suppression of APC/C activity during interphase of mouse pluripotent cells promotes rapid cell cycle progression by allowing stabilization of cyclins, whereas unopposed APC/C activity during S phase of mouse trophoblast cells triggers proteasomal-mediated degradation of geminin and giant cell formation. While differential APC/C activity might govern the atypical cell cycles observed in pre-implantation mouse embryos, geminin is a critical APC/C substrate that: (1) escapes degradation in pluripotent cells to maintain expression of Oct4, Sox2 and Nanog; and (2) mediates specification and endoreduplication when targeted for ectopic destruction in trophoblast. Thus, in contrast to trophoblast giant cells that lack geminin, geminin is preserved in both mouse pluripotent cells and non-endoreduplicating human cytotrophoblast cells.


Assuntos
Complexos Ubiquitina-Proteína Ligase/metabolismo , Ciclossomo-Complexo Promotor de Anáfase , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Ciclina A2/metabolismo , Ciclina B1/metabolismo , Células-Tronco Embrionárias/metabolismo , Endorreduplicação , Geminina , Humanos , Interfase , Camundongos , Mitose , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Células-Tronco Pluripotentes/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/genética , Proteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Trofoblastos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
3.
Curr Biol ; 21(8): 692-9, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21497086

RESUMO

Geminin is an essential cell-cycle protein that is only present from S phase to early mitosis in metazoan somatic cells. Genetic ablation of geminin in the mouse results in preimplantation embryonic lethality because pluripotent cells fail to form and all cells differentiate to trophoblast. Here we show that geminin is present in G1 phase of mouse pluripotent cells in contrast to somatic cells, where anaphase-promoting complex/cyclosome (APC/C)-mediated proteasomal destruction removes geminin in G1. Silencing geminin directly or by depleting the APC/C inhibitor Emi1 causes loss of stem cell identity and trophoblast differentiation of mouse embryonal carcinoma and embryonic stem cells. Depletion of cyclins A2 or B1 does not induce this effect, even though both of these APC/C substrates are also present during G1 of pluripotent cells. Crucially, geminin antagonizes the chromatin-remodeling protein Brg1 to maintain expression of Oct4, Sox2, and Nanog. Our results define a pluripotency pathway by which suppressed APC/C activity protects geminin from degradation in G1, allowing sustained expression of core pluripotency factors. Collectively, these findings link the cell cycle to the pluripotent state but also raise an unexplained paradox: How is cell-cycle progression possible in pluripotent cells when oscillations of key regulatory proteins are lost?


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fase G1 , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/metabolismo , Ciclossomo-Complexo Promotor de Anáfase , Animais , Diferenciação Celular , Ciclina A2/metabolismo , Ciclina B1/metabolismo , DNA Helicases/metabolismo , Células-Tronco de Carcinoma Embrionário/citologia , Células-Tronco Embrionárias/citologia , Geminina , Camundongos , Proteína Homeobox Nanog , Complexos Ubiquitina-Proteína Ligase/metabolismo
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