Abstract
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.
Highlights
NOTCH signaling controls cell proliferation, differentiation, and apoptosis
In addition to RBP-Jκ/ NOTCH Intracellular Cleaved Domain (NICD)/MAML1, other regulators are required for the measured activation of NOTCH target genes
Since it can favor transcriptional activation and control gene expression levels, we questioned whether IKAROS could participate to the activation of specific NOTCH target genes
Summary
NOTCH signaling controls cell proliferation, differentiation, and apoptosis. It is required for hematopoietic stem/progenitor cells (HS/PC) interactions with their environment [1,2]. In mammalian cells different transcription factors including members of the IKZF family such as IKAROS (IKZF1), HELIOS (IKZF2) and AIOLOS (IKZF3) were reported to interact with NICD [7,8]. Whether these interactions can be functional and stabilize RBP-Jκ/NICD at specific genes is not known
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