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The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation

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Abstract

Krueppel-like factor 4 (Klf4) belongs to the Sp/Klf family of zinc-finger transcription factors and is indispensable for terminal maturation of epithelial tissues. Furthermore, it is part of a small set of proteins that are used to generate pluripotent embryonic stem cells from differentiated tissues. Herein, we describe that a Klf4 zinc-finger domain mutant induces self-renewal and block of maturation, while wild-type Klf4 induces terminal macrophage differentiation. Moreover, we present the crystal structure of the zinc-finger domain of Klf4 bound to its target DNA, revealing that primarily the two C-terminal zinc-finger motifs are required for site specificity. Lack of those two zinc fingers leads to deficiency of Klf4 to induce macrophage differentiation. The first zinc finger, on the other hand, inhibits the otherwise cryptic self-renewal and block of differentiation activity of Klf4. Our data show that impairing the DNA binding could potentially contribute to a monocytic leukemia.

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Abbreviations

Klf4:

Krueppel-like factor 4

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft to D.C. (CA 306/1-1; 1-2) and the “Deutsche Krebshilfe” to D.C. The Protein Sample Production Facility at the Max Delbrück Center is funded by the Helmholtz Association of German Research Centres. We thank Janett Tischer, Silke Kurths, Ingrid Berger, and Tracy Dornblut for excellent technical assistance. We are also thankful to the kind staff of the cell sorting facility of the Deutsche Rheumaforschungszentrum and acknowledge Uwe Müller and the beamline support from the staff of Helmholtz-Zentrum Berlin für Materialien und Energie at BESSY.

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Author notes

  1. Georg Zocher

    Present address: Interfakultäres Institut für Biochemie, Eberhard-Karls-Universität Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany

Authors and Affiliations

  1. Protein Sample Production Facility, Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Anja Schuetz & Udo Heinemann

  2. Leibniz-Institut für Molekulare Pharmakologie (FMP), Krahmerstr. 6, 12207, Berlin, Germany

    Didier Nana, Charlotte Rose, Maja Milanovic, Jessica Koenigsmann, Rosel Blasig & Dirk Carstanjen

  3. Helmholtz-Zentrum Berlin für Materialien und Energie GmbH, Albert-Einstein-Str. 15, 12489, Berlin, Germany

    Georg Zocher

  4. Institut für Biochemie, Freie Universität Berlin, Takustr. 6, 14095, Berlin, Germany

    Udo Heinemann

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  1. Anja Schuetz
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Correspondence to Dirk Carstanjen.

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Schuetz, A., Nana, D., Rose, C. et al. The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell. Mol. Life Sci. 68, 3121–3131 (2011). https://doi.org/10.1007/s00018-010-0618-x

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  • DOI: https://doi.org/10.1007/s00018-010-0618-x

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