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IKAROS: from chromatin organization to transcriptional elongation control

Cell Death & Differentiation (2023)Cite this article

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Abstract

IKAROS is a master regulator of cell fate determination in lymphoid and other hematopoietic cells. This transcription factor orchestrates the association of epigenetic regulators with chromatin, ensuring the expression pattern of target genes in a developmental and lineage-specific manner. Disruption of IKAROS function has been associated with the development of acute lymphocytic leukemia, lymphoma, chronic myeloid leukemia and immune disorders. Paradoxically, while IKAROS has been shown to be a tumor suppressor, it has also been identified as a key therapeutic target in the treatment of various forms of hematological malignancies, including multiple myeloma. Indeed, targeted proteolysis of IKAROS is associated with decreased proliferation and increased death of malignant cells. Although the molecular mechanisms have not been elucidated, the expression levels of IKAROS are variable during hematopoiesis and could therefore be a key determinant in explaining how its absence can have seemingly opposite effects. Mechanistically, IKAROS collaborates with a variety of proteins and complexes controlling chromatin organization at gene regulatory regions, including the Nucleosome Remodeling and Deacetylase complex, and may facilitate transcriptional repression or activation of specific genes. Several transcriptional regulatory functions of IKAROS have been proposed. An emerging mechanism of action involves the ability of IKAROS to promote gene repression or activation through its interaction with the RNA polymerase II machinery, which influences pausing and productive transcription at specific genes. This control appears to be influenced by IKAROS expression levels and isoform production. In here, we summarize the current state of knowledge about the biological roles and mechanisms by which IKAROS regulates gene expression. We highlight the dynamic regulation of this factor by post-translational modifications. Finally, potential avenues to explain how IKAROS destruction may be favorable in the treatment of certain hematological malignancies are also explored.

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Fig. 1: IKZF family of transcription factors.
Fig. 2: IKAROS isoforms and effect of dimerization.
Fig. 3: IKAROS missense mutations in hematopoietic disorders.
Fig. 4: IKAROS interactome.
Fig. 5: IKAROS post-translational modifications.
Fig. 6: IKAROS and AIOLOS degradation upon treatment with immunomodulatory imide drugs (IMiDs).
Fig. 7: Crosstalk between IKAROS missense mutations, PTMs and interactome.
Fig. 8: The influence of IKAROS over gene regulation extends from chromatin organization to transcriptional elongation.

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Acknowledgements

We thank the laboratory members for useful discussions.

Funding

Funding

The author’s work is supported by grants from the Canadian Institute of Health Research (CIHR PJT - 180491) held by EM and by the the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2021-04110) held by EBA; MA was supported by the internship awards from NSERC and from PREMIER of the faculty of Medicine, Université de Montréal.

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  1. These authors contributed equally: Malik Affar, Stefania Bottardi.

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  1. Faculty of Medicine, University of Montreal, Montréal, QC, Canada

    Malik Affar, Maud Lemarié, Ailyn C. Ramón, El Bachir Affar & Eric Milot

  2. Maisonneuve-Rosemont Hospital Research Center, CIUSSS de l’Est-de-l’Île de Montréal, 5415 boulevard de l’Assomption, Montréal, QC, H1T 2M4, Canada

    Malik Affar, Stefania Bottardi, Norreen Quansah, Maud Lemarié, Ailyn C. Ramón, El Bachir Affar & Eric Milot

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SB, MA, EBA, and EM, designed and wrote the manuscript. NQ, ACR and ML participate in the writing of specific sections of the manuscript and with Table 1. The authors approved the final manuscript.

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Affar, M., Bottardi, S., Quansah, N. et al. IKAROS: from chromatin organization to transcriptional elongation control. Cell Death Differ (2023). https://doi.org/10.1038/s41418-023-01212-2

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