Role of Ikaros in repressing the Notch target gene Hes-1 during T cell differentiation

Les protéines Ikaros et Notch ont toutes deux été impliquées de façon indépendante dans le développement de lymphomes T chez l'homme et la souris. Chez les souris portant une mutation pour Ikaros, le développement de lymphomes T est toujours associé à une surexpression précoce de la voie Notch dans les thymocytes. Ikaros et de RBP-Jk reconnaissent des séquences in vivo dans des cellules DN, suggérant une fixation séquentielle des deux facteurs au cours de la transition DN3-DN4. Au niveau chromatinien, les cellules DP IkL/L'présentent une altération des modifications répressives d'histones au niveau du promoteur Hes-1. Ces résultats suggèrent que la compétition entre Ikaros et RBP-Jk semble être un mécanisme central de la régulation des gènes dans les cellules T. L'extinction des gènes cibles de Notch par Ikaros est nécessaire à la différenciation des thymocytes et la dérégulation de ce mécanisme pourrait être l'une des causes du développement de leucémies T en l'absence d'Ikaros.Ikaros and Notch have been found independently to be involved in T lymphogenesis in mouse and man. In mice bearing a hypomorphic mutation in Ikaros, T lymphoma development is associated with early Notch target gene overexpression in thymocytes. Ikaros and RBP-Jk bind to Hes-1 promoter sequences in vitro in a specific and mutually exclusive manner. Both proteins recognise regions containing those Hes-1 promoter sequences in vivo in DN cells, suggesting the sequential binding of both factors during the DN3-DN4 transition. At the chromatin level, IkL/L DP cells lack repressive histone modifications at the Hes-1 promoter. To conclude, these results suggest that competition between Ikaros and RBP-Jk may be a central mechanism in regulating T cell genes. Notch target gene silencing by Ikaros is essential to thymocyte differentiation and deregulation in this mechanism could in absence of Ikaros cause T leukemic development

Role of Ikaros in repressing the Notch target gene Hes-1 during T cell differentiation

Les protéines Ikaros et Notch ont toutes deux été impliquées de façon indépendante dans le développement de lymphomes T chez l'homme et la souris. Chez les souris portant une mutation pour Ikaros, le développement de lymphomes T est toujours associé à uneIkaros and Notch have been found independently to be involved in T lymphogenesis in mouse and man. In mice bearing a hypomorphic mutation in Ikaros, T lymphoma development is associated with early Notch target gene overexpression in thymocytes. Ikaros an

Role of Ikaros in repressing the Notch target gene Hes-1 during T cell differentiation

Les protéines Ikaros et Notch ont toutes deux été impliquées de façon indépendante dans le développement de lymphomes T. Chez les souris portant une mutation hypomorphe pour Ikaros, le développement de lymphomes T est toujours associé à une surexpression précoce de la voie Notch dans les thymocytes pré-tumoraux. Ikaros et RBP-Jk reconnaissent les mêmes régions in vivo dans les thymocytes immatures, suggérant une fixation séquentielle des deux facteurs au cours de la différenciation des cellules T. Au niveau chromatinien, les cellules DP IkL/L présentent une altération des modifications répressives d’histones au niveau du promoteur Hes-1, suggérant un rôle d’Ikaros dans la méthylation de résidus associés à l’extinction de gènes. Ces résultats suggèrent que l’extinction des gènes cibles de Notch par Ikaros, via la compétition avec RBP-Jk, est nécessaire à la différenciation des thymocytes, et la dérégulation de ce mécanisme pourrait être l’une des causes de la transformation des cellules T en l’absence d’Ikaros.Ikaros and Notch have been found independently to be involved in T lymphogenesis in mouse and man. In mice bearing a hypomorphic mutation in Ikaros, T lymphoma development is associated with early Notch target gene overexpression in pre-malignant thymocytes. Ikaros and RBP-Jk bind to Hes-1 promoter sequences in vitro in a specific and mutually exclusive manner. Both proteins recognise regions containing these sequences in vivo in immature thymocytes, suggesting the sequential binding of both factors during T-cell differentiation. At the chromatin level, IkL/L thymocytes DP cells lack repressive histone modifications at the Hes-1 promoter, suggesting that Ikaros may be responsible for the methylation of residues associated with gene silencing. These results suggest that Notch target gene silencing by Ikaros, through competition with RBP-Jk, is essential for to thymocyte differentiation, and that deregulation of this mechanism in absence of Ikaros may induce T cell transformation

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development ▿ †

Notch activity is essential for early T-cell differentiation, but aberrant activity induces T-cell transformation. Thus, Notch target genes must be efficiently silenced in cells where Notch activity is no longer required. How these genes are repressed remains poorly understood. We report here that the Ikaros transcription factor plays a crucial role in repressing the transcriptional response to Notch signaling in T-cell development. Using the Notch target gene Hes-1 as a model, we show that Ikaros and RBP-Jκ, the transcriptional mediator of Notch signaling, compete for binding to two elements in the Hes-1 promoter in immature thymocytes. This antagonistic interaction likely occurs at the CD4− CD8− CD3− double-negative 4 (DN4) stage, where Ikaros levels and binding to the Hes-1 promoter increase sharply and wild-type thymocytes lose their capacity to transcribe Hes-1 upon Notch stimulation. Nonresponsiveness to Notch signaling requires Ikaros, as Ikaros-deficient DN4 and CD4+ CD8+ double-positive (DP) cells remain competent to express Hes-1 after Notch activation. Further, Hes-1 promoter sequences from Ikaros-deficient DP cells show reduced trimethylated H3K27, a modification associated with silent chromatin. These results indicate that Ikaros functions as a transcriptional checkpoint to repress Notch target gene expression in T cells

Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik(L/L)) in the Ikaros gene all develop thymic lymphomas. Ik(L/L) tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young Ik(L/L) mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor