title: The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation.
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.
authors.affiliation: Protein Sample Production Facility, Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schuetz
authors.forename: Didier
authors.initials: D
authors.lastname: Nana
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rose
authors.forename: Georg
authors.initials: G
authors.lastname: Zocher
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.forename: Jessica
authors.initials: J
authors.lastname: Koenigsmann
authors.forename: Rosel
authors.initials: R
authors.lastname: Blasig
authors.forename: Udo
authors.initials: U
authors.lastname: Heinemann
authors.forename: Dirk
authors.initials: D
authors.lastname: Carstanjen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003114:Colony-Forming Units Assay; D003460:Crystallization; D004247:DNA / Q000378:metabolism*; D005434:Flow Cytometry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007948:Leukemia, Monocytic, Acute / Q000209:etiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D012190:Retroviridae; D014961:X-Ray Diffraction; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D004247:DNA