The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells.
Sci Signal, 2014/3/18;7(317):ra28.
Geimer Le Lay AS[1], Oravecz A, Mastio J, Jung C, Marchal P, Ebel C, Dembélé D, Jost B, Le Gras S, Thibault C, Borggrefe T, Kastner P, Chan S
Affiliations
PMID: 24643801DOI: 10.1126/scisignal.2004545
Impact factor: 9.517
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.
MeSH terms
Chromatin; Gene Expression Regulation; Genes, Tumor Suppressor; Humans; Ikaros Transcription Factor; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Receptors, Notch; Regulatory Sequences, Nucleic Acid; T-Lymphocytes; Transcription, Genetic
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