A unique Oct4 interface is crucial for reprogramming to pluripotency
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A unique Oct4 interface is crucial for reprogramming to pluripotency. / Esch, Daniel; Vahokoski, Juha; Groves, Matthew R; Pogenberg, Vivian; Cojocaru, Vlad; Vom Bruch, Hermann; Han, Dong; Drexler, Hannes C A; Araúzo-Bravo, Marcos J; Ng, Calista K L; Jauch, Ralf; Wilmanns, Matthias; Schöler, Hans R.
in: NAT CELL BIOL, Jahrgang 15, Nr. 3, 03.2013, S. 295-301.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A unique Oct4 interface is crucial for reprogramming to pluripotency
AU - Esch, Daniel
AU - Vahokoski, Juha
AU - Groves, Matthew R
AU - Pogenberg, Vivian
AU - Cojocaru, Vlad
AU - Vom Bruch, Hermann
AU - Han, Dong
AU - Drexler, Hannes C A
AU - Araúzo-Bravo, Marcos J
AU - Ng, Calista K L
AU - Jauch, Ralf
AU - Wilmanns, Matthias
AU - Schöler, Hans R
PY - 2013/3
Y1 - 2013/3
N2 - Terminally differentiated cells can be reprogrammed to pluripotency by the forced expression of Oct4, Sox2, Klf4 and c-Myc. However, it remains unknown how this leads to the multitude of epigenetic changes observed during the reprogramming process. Interestingly, Oct4 is the only factor that cannot be replaced by other members of the same family to induce pluripotency. To understand the unique role of Oct4 in reprogramming, we determined the structure of its POU domain bound to DNA. We show that the linker between the two DNA-binding domains is structured as an α-helix and exposed to the protein's surface, in contrast to the unstructured linker of Oct1. Point mutations in this α-helix alter or abolish the reprogramming activity of Oct4, but do not affect its other fundamental properties. On the basis of mass spectrometry studies of the interactome of wild-type and mutant Oct4, we propose that the linker functions as a protein-protein interaction interface and plays a crucial role during reprogramming by recruiting key epigenetic players to Oct4 target genes. Thus, we provide molecular insights to explain how Oct4 contributes to the reprogramming process.
AB - Terminally differentiated cells can be reprogrammed to pluripotency by the forced expression of Oct4, Sox2, Klf4 and c-Myc. However, it remains unknown how this leads to the multitude of epigenetic changes observed during the reprogramming process. Interestingly, Oct4 is the only factor that cannot be replaced by other members of the same family to induce pluripotency. To understand the unique role of Oct4 in reprogramming, we determined the structure of its POU domain bound to DNA. We show that the linker between the two DNA-binding domains is structured as an α-helix and exposed to the protein's surface, in contrast to the unstructured linker of Oct1. Point mutations in this α-helix alter or abolish the reprogramming activity of Oct4, but do not affect its other fundamental properties. On the basis of mass spectrometry studies of the interactome of wild-type and mutant Oct4, we propose that the linker functions as a protein-protein interaction interface and plays a crucial role during reprogramming by recruiting key epigenetic players to Oct4 target genes. Thus, we provide molecular insights to explain how Oct4 contributes to the reprogramming process.
KW - Amino Acid Sequence
KW - Animals
KW - Blotting, Western
KW - Cell Differentiation
KW - Cells, Cultured
KW - Cellular Reprogramming
KW - Crystallography, X-Ray
KW - DNA/genetics
KW - Electrophoretic Mobility Shift Assay
KW - Embryonic Stem Cells/cytology
KW - Epigenesis, Genetic
KW - Fibroblasts/cytology
KW - Humans
KW - Luciferases/metabolism
KW - Mice
KW - Molecular Sequence Data
KW - Octamer Transcription Factor-3/chemistry
KW - Pluripotent Stem Cells/cytology
KW - RNA, Messenger/genetics
KW - Real-Time Polymerase Chain Reaction
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Sequence Homology, Amino Acid
KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
U2 - 10.1038/ncb2680
DO - 10.1038/ncb2680
M3 - SCORING: Journal article
C2 - 23376973
VL - 15
SP - 295
EP - 301
JO - NAT CELL BIOL
JF - NAT CELL BIOL
SN - 1465-7392
IS - 3
ER -