title: The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells.
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.
authors.affiliation: 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Anne-Solen
authors.initials: AS
authors.lastname: Geimer Le Lay
authors.forename: Attila
authors.initials: A
authors.lastname: Oravecz
authors.forename: Jérôme
authors.initials: J
authors.lastname: Mastio
authors.forename: Claudia
authors.initials: C
authors.lastname: Jung
authors.forename: Patricia
authors.initials: P
authors.lastname: Marchal
authors.forename: Claudine
authors.initials: C
authors.lastname: Ebel
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Gras
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Tilman
authors.initials: T
authors.lastname: Borggrefe
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
mesh_terms: D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism / Q000502:physiology*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C497239:IKZF1 protein, human; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D051880:Receptors, Notch; D051740:Ikaros Transcription Factor