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Molecular and Cellular Biology, December 2008, p. 7465-7475, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00715-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development {triangledown} ,{dagger}

Eva Kleinmann, Anne-Solen Geimer Le Lay, MacLean Sellars, Philippe Kastner,* and Susan Chan*

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Cancer Biology, Illkirch F-67400, France; Inserm U596, Illkirch F-67400, France; CNRS UMR7104, Illkirch F-67400, France; and Université Louis Pasteur, Strasbourg F-67000, France

Received 2 May 2008/ Returned for modification 11 June 2008/ Accepted 28 September 2008

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-J{kappa}, 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.

* Corresponding author. Mailing address: IGBMC, BP 10142, 67404 Illkirch Cedex, France. Phone: 33-3-88-65-34-61. Fax: 33-3-88-65-32-01. E-mail: scpk{at}igbmc.u-strasbg.fr

{triangledown} Published ahead of print on 13 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7465-7475, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00715-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sellars, M., Reina-San-Martin, B., Kastner, P., Chan, S. (2009). Ikaros controls isotype selection during immunoglobulin class switch recombination. JEM 206: 1073-1087 [Abstract] [Full Text]  


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