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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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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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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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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DOI: https://doi.org/10.1038/ni.2707
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