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IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling


Autoři: Maud Lemarié aff001;  Stefania Bottardi aff001;  Lionel Mavoungou aff001;  Helen Pak aff001;  Eric Milot aff001
Působiště autorů: Maisonneuve-Rosemont Hospital Research Center; CIUSSS de l’est de l’Île de Montréal, Montréal, QC, Canada aff001;  Department of Medicine, Université de Montréal, Montréal, Québec, Canada aff002
Vyšlo v časopise: IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling. PLoS Genet 17(3): e1009478. doi:10.1371/journal.pgen.1009478
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009478

Souhrn

The tumor suppressor IKAROS binds and represses multiple NOTCH target genes. For their induction upon NOTCH signaling, IKAROS is removed and replaced by NOTCH Intracellular Domain (NICD)-associated proteins. However, IKAROS remains associated to other NOTCH activated genes upon signaling and induction. Whether IKAROS could participate to the induction of this second group of NOTCH activated genes is unknown. We analyzed the combined effect of IKAROS abrogation and NOTCH signaling on the expression of NOTCH activated genes in erythroid cells. In IKAROS-deleted cells, we observed that many of these genes were either overexpressed or no longer responsive to NOTCH signaling. IKAROS is then required for the organization of bivalent chromatin and poised transcription of NOTCH activated genes belonging to either of the aforementioned groups. Furthermore, we show that IKAROS-dependent poised organization of the NOTCH target Cdkn1a is also required for its adequate induction upon genotoxic insults. These results highlight the critical role played by IKAROS in establishing bivalent chromatin and transcriptional poised state at target genes for their activation by NOTCH or other stress signals.

Klíčová slova:

DNA transcription – Gene expression – Gene regulation – Chromatin – Chromatin immunoprecipitation – Immunoprecipitation – Notch signaling – Tumor suppressor genes


Zdroje

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