Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Dev Cell ; 55(5): 544-557.e6, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33120014

RESUMO

Differentiation therapy utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift toward terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have met with limited success. Mammary-specific activation of PKA in mouse models leads to aberrant differentiation and diminished self-renewing potential of the basal compartment, which harbors mammary repopulating cells. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential, and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single-cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. Acting through the repression of SOX4, PKA activation promotes tumor differentiation and represents a possible adjuvant to chemotherapy for certain breast cancers.


Assuntos
Diferenciação Celular , Autorrenovação Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem da Célula , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Feminino , Amplificação de Genes , Loci Gênicos , Genoma Humano , Humanos , Neoplasias Mamárias Animais/genética , Camundongos , Metástase Neoplásica , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais
2.
Genome Res ; 26(11): 1505-1519, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27650846

RESUMO

Cell lineages, which shape the body architecture and specify cell functions, derive from the integration of a plethora of cell intrinsic and extrinsic signals. These signals trigger a multiplicity of decisions at several levels to modulate the activity of dynamic gene regulatory networks (GRNs), which ensure both general and cell-specific functions within a given lineage, thereby establishing cell fates. Significant knowledge about these events and the involved key drivers comes from homogeneous cell differentiation models. Even a single chemical trigger, such as the morphogen all-trans retinoic acid (RA), can induce the complex network of gene-regulatory decisions that matures a stem/precursor cell to a particular step within a given lineage. Here we have dissected the GRNs involved in the RA-induced neuronal or endodermal cell fate specification by integrating dynamic RXRA binding, chromatin accessibility, epigenetic promoter epigenetic status, and the transcriptional activity inferred from RNA polymerase II mapping and transcription profiling. Our data reveal how RA induces a network of transcription factors (TFs), which direct the temporal organization of cognate GRNs, thereby driving neuronal/endodermal cell fate specification. Modeling signal transduction propagation using the reconstructed GRNs indicated critical TFs for neuronal cell fate specification, which were confirmed by CRISPR/Cas9-mediated genome editing. Overall, this study demonstrates that a systems view of cell fate specification combined with computational signal transduction models provides the necessary insight in cellular plasticity for cell fate engineering. The present integrated approach can be used to monitor the in vitro capacity of (engineered) cells/tissues to establish cell lineages for regenerative medicine.


Assuntos
Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Neurogênese , Animais , Linhagem Celular Tumoral , Linhagem da Célula , Cromatina/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Endoderma/citologia , Epigênese Genética , Camundongos , Ativação Transcricional , Tretinoína/farmacologia
3.
Nucleic Acids Res ; 41(21): e196, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24038469

RESUMO

The absence of a quality control (QC) system is a major weakness for the comparative analysis of genome-wide profiles generated by next-generation sequencing (NGS). This concerns particularly genome binding/occupancy profiling assays like chromatin immunoprecipitation (ChIP-seq) but also related enrichment-based studies like methylated DNA immunoprecipitation/methylated DNA binding domain sequencing, global run on sequencing or RNA-seq. Importantly, QC assessment may significantly improve multidimensional comparisons that have great promise for extracting information from combinatorial analyses of the global profiles established for chromatin modifications, the bindings of epigenetic and chromatin-modifying enzymes/machineries, RNA polymerases and transcription factors and total, nascent or ribosome-bound RNAs. Here we present an approach that associates global and local QC indicators to ChIP-seq data sets as well as to a variety of enrichment-based studies by NGS. This QC system was used to certify >5600 publicly available data sets, hosted in a database for data mining and comparative QC analyses.


Assuntos
Imunoprecipitação da Cromatina/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Análise de Sequência de DNA/normas , Simulação por Computador , Controle de Qualidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA