The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells.
Sci Signal
; 7(317): ra28, 2014 Mar 18.
Article
em En
| MEDLINE
| ID: mdl-24643801
ABSTRACT
The Notch signaling pathway is activated in many cell types, but its effects are cell type- and stage-specific. In the immune system, Notch activity is required for the differentiation of T cell progenitors, but it is reduced in more mature thymocytes, in which Notch is oncogenic. Studies based on single-gene models have suggested that the tumor suppressor protein Ikaros plays an important role in repressing the transcription of Notch target genes. We used genome-wide analyses, including chromatin immunoprecipitation sequencing, to identify genes controlled by Notch and Ikaros in gain- and loss-of-function experiments. We found that Ikaros bound to and directly repressed the expression of most genes that are activated by Notch. Specific deletion of Ikaros in thymocytes led to the persistent expression of Notch target genes that are essential for T cell maturation, as well as the rapid development of T cell leukemias in mice. Expression of Notch target genes that are normally silent in T cells, but are activated by Notch in other cell types, occurred in T cells of mice genetically deficient in Ikaros. We propose that Ikaros shapes the timing and repertoire of the Notch transcriptional response in T cells through widespread targeting of elements adjacent to Notch regulatory sequences. These results provide a molecular framework for understanding the regulation of tissue-specific and tumor-related Notch responses.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Genes Supressores de Tumor
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Fator de Transcrição Ikaros
/
Receptores Notch
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article