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1.
Proc Natl Acad Sci U S A ; 105(37): 14076-81, 2008 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-18780791

RESUMO

Cellular identity and differentiation are determined by epigenetic programs. The characteristics of these programs in normal human mammary epithelium and their similarity to those in stem cells are unknown. To begin investigating these issues, we analyzed the DNA methylation and gene expression profiles of distinct subpopulations of mammary epithelial cells by using MSDK (methylation-specific digital karyotyping) and SAGE (serial analysis of gene expression). We identified discrete cell-type and differentiation state-specific DNA methylation and gene expression patterns that were maintained in a subset of breast carcinomas and correlated with clinically relevant tumor subtypes. CD44+ cells were the most hypomethylated and highly expressed several transcription factors with known stem cell function including HOXA10 and TCF3. Many of these genes were also hypomethylated in BMP4-treated compared with undifferentiated human embryonic stem (ES) cells that we analyzed by MSDK for comparison. Further highlighting the similarity of epigenetic programs of embryonic and mammary epithelial cells, genes highly expressed in CD44+ relative to more differentiated CD24+ cells were significantly enriched for Suz12 targets in ES cells. The expression of FOXC1, one of the transcription factors hypomethylated and highly expressed in CD44+ cells, induced a progenitor-like phenotype in differentiated mammary epithelial cells. These data suggest that epigenetically controlled transcription factors play a key role in regulating mammary epithelial cell phenotypes and imply similarities among epigenetic programs that define progenitor cell characteristics.


Assuntos
Mama/metabolismo , Metilação de DNA , Mama/citologia , Contagem de Células , Forma Celular , Células Epiteliais/citologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Fenótipo , Células-Tronco/metabolismo , Especificidade por Substrato
2.
Proc Natl Acad Sci U S A ; 100(23): 13350-5, 2003 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-14595015

RESUMO

Remarkably little is known about the transcriptional profiles of human embryonic stem (ES) cells or the molecular mechanisms that underlie their pluripotency. To identify commonalties among the transcriptional profiles of different human pluripotent cells and to search for clues into the genesis of human germ cell tumors, we compared the expression profiles of human ES cell lines, human germ cell tumor cell lines and tumor samples, somatic cell lines, and testicular tissue samples by using cDNA microarray analysis. Hierarchical cluster analysis of gene expression profiles showed that the five independent human ES cell lines clustered tightly together, reflecting highly similar expression profiles. The gene expression patterns of human ES cell lines showed many similarities with the human embryonal carcinoma cell samples and more distantly with the seminoma samples. We identified 895 genes that were expressed at significantly greater levels in human ES and embryonal carcinoma cell lines than in control samples. These genes are candidates for involvement in the maintenance of a pluripotent, undifferentiated phenotype.


Assuntos
Carcinoma Embrionário/metabolismo , Embrião de Mamíferos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Neoplasias Embrionárias de Células Germinativas/metabolismo , Células-Tronco/metabolismo , Carcinoma Embrionário/genética , Diferenciação Celular , Mapeamento Cromossômico , Análise por Conglomerados , DNA Complementar/metabolismo , Regulação para Baixo , Células-Tronco de Carcinoma Embrionário , Humanos , Neoplasias Embrionárias de Células Germinativas/genética , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , RNA Mensageiro/metabolismo , Seminoma/genética , Regulação para Cima
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