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Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros

Nature Immunology volume 14, pages 1073–1083 (2013)Cite this article

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Abstract

C2H2 zinc fingers are found in several key transcriptional regulators in the immune system. However, these proteins usually contain more fingers than are needed for sequence-specific DNA binding, which suggests that different fingers regulate different genes and functions. Here we found that mice lacking finger 1 or finger 4 of Ikaros exhibited distinct subsets of the hematological defects of Ikaros-null mice. Most notably, the two fingers controlled different stages of lymphopoiesis, and finger 4 was selectively required for tumor suppression. The distinct defects support the hypothesis that only a small number of genes that are targets of Ikaros are critical for each of its biological functions. The subcategorization of functions and target genes by mutagenesis of individual zinc fingers will facilitate efforts to understand how zinc-finger transcription factors regulate development, immunity and disease.

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Figure 1: Adult B cells are present in mice with germline deletion of Ikzf1 exons encoding zinc-finger 1 or 4.
Figure 2: B cell development is disrupted at different stages in Ikzf1ΔF1/ΔF1 and Ikzf1ΔF4/ΔF4 mice.
Figure 3: Selective thymocyte and fetal phenotypes in Ikzf1ΔF1/ΔF1 and Ikzf1ΔF4/ΔF4 mice.
Figure 4: Differences in the binding of Ikaros to DNA in Ikzf1ΔF1/ΔF1 and Ikzf1ΔF4/ΔF4 thymocytes.
Figure 5: Deregulation of distinct sets of genes in Ikzf1ΔF1/ΔF1 and Ikzf1ΔF4/ΔF4 DP thymocytes.
Figure 6: Ikzf1ΔF4/ΔF4 mice develop spontaneous thymic lymphoma but Ikzf1ΔF1/ΔF1 mice do not.
Figure 7: Selective synergy between BCR-ABL and the Ikzf1ΔF4/ΔF4 mutation in vitro and in vivo.

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Acknowledgements

We thank P. Aliahmad, D. Bhatt, K. Dorshkind, C. Li and E. Montecino-Rodriguez for advice and/or critical reading of the manuscript; the Division of Laboratory Animal Medicine of the University of California, Los Angeles, for ongoing care of mice; and H. Mak, T. Jacob, C. Garcia, J. Flores and J. Lorenzano for assistance with the mouse colony. ChIP-seq and RNA-Seq libraries were sequenced at the Epigenome Data Production Facility of the University of Southern California, and the Broad Stem Cell Research Center High Throughput Sequencing Core of the University of California, Los Angeles. Supported by the US National Institutes of Health (RO1DK043726 to S.T.S. and U54HG004558 to P.J.F.). O.N.W. is an Investigator of the Howard Hughes Medical Institute.

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  1. Hilde Schjerven & Seth Frietze

    Present address: Present addresses: Department of Laboratory Medicine, University of California, San Francisco, California, USA (H.S.), and School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA (S.F.).,

Authors and Affiliations

  1. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA

    Hilde Schjerven, Jami McLaughlin, Teresita L Arenzana, Donghui Cheng, Sarah E Wadsworth, Owen N Witte & Stephen T Smale

  2. Molecular Biology Institute, University of California, Los Angeles, California, USA

    Hilde Schjerven, Teresita L Arenzana, Sarah E Wadsworth, Steven J Bensinger, Owen N Witte & Stephen T Smale

  3. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA

    Seth Frietze & Peggy J Farnham

  4. Howard Hughes Medical Institute, University of California, Los Angeles, California, USA

    Donghui Cheng & Owen N Witte

  5. Division of Laboratory Animal Medicine, University of California, Los Angeles, California, USA

    Gregory W Lawson

  6. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA

    Gregory W Lawson & Steven J Bensinger

  7. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California, USA

    Owen N Witte & Stephen T Smale

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Contributions

H.S., J.M., T.L.A., S.F., D.C., S.E.W. and G.W.L. designed and did experiments and analyzed data; S.J.B. provided intellectual input and experimental advice; P.J.F., O.N.W. and S.T.S. supervised research and analyzed data; and H.S. and S.T.S. wrote the manuscript.

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Correspondence to Stephen T Smale.

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Schjerven, H., McLaughlin, J., Arenzana, T. et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nat Immunol 14, 1073–1083 (2013). https://doi.org/10.1038/ni.2707

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