New study sheds light on cellular reprogramming
3D structure of Oct4 (in green) bound to DNA helix. The linker is shown in red.
Credit: EMBL/Vivian Pogenberg
In a nutshell:
The transcription factor Oct4 controls the genes involved in reprogramming mature cells to become pluripotent again
The 3D structure of a particular linker sequence within Oct4 sheds light on how the transcription factor interacts with its target genes
A better understanding of the reprogramming of cells may pave the way for new applications in regenerative medicine and drug discovery.
Mature cells can be reprogrammed to pluripotency and thus regain the ability to divide and differentiate into specialized cell types. Although these so-called induced pluripotent stem cells (iPS cells) represent a milestone in stem cell research, many of the biochemical processes that underlie reprogramming are still not understood. Scientists from the EMBL Hamburg and from the Max Planck Institute for Molecular Biomedicine in Münster, Germany now shed new light on this process. In a study published today in Nature Cell Biology, the scientists describe important details about the structure of the transcription factor Oct4, known to play a crucial role in the reprogramming of terminally differentiated cells. The study broadens the knowledge about the reprogramming of cells and may pave the way for medical applications in the field of regenerative medicine and drug discovery.
The transcription factor Oct4 is a protein that binds to DNA and controls the genes involved in reprogramming the cells. The team at EMBL Hamburg has now been able to resolve the crystal structure of Oct4 using high-intensity X-ray beams. In particular, their analysis focused on a previously unexplored linker sequence between two DNA binding elements of the protein. “The uniqueness of the linker has caught our attention for more than a decade and, thus, we are extremely pleased to see it for the first time, helping us rationalize its function in reprogramming cells to pluripotency” says Matthias Wilmanns who led the work in Hamburg.
The authors suggest that the linker recruits key partners to the Oct4 target genes, without whom the process of reprogramming cannot be completed. Colleagues at the Max Planck Institute for Molecular Biomedicine led by Hans Schöler supported these findings with studies on the modifications of the linker. They showed that changes in the sequence of the linker led to the loss of Oct4’s reprogramming activity, and that a single residue mutation has major effects on the protein interface and thus affects the recruiting of key partners.
“Our work shows how unique the Oct4 interface is and how crucial it is for reprogramming to pluripotency. These are vital steps forward in our understanding of cell reprogramming and could lead us to new applications in the fields of drug discovery and tissue engineering” said Hans Schöler.
Ongoing research will help determine an integrated picture on how Oct4 acts in the context of many other protein components in stem cell pluripotency.
A unique Oct4 interface is crucial for reprogramming to pluripotency - Daniel Esch, Juha Vahokoski, Matthew R. Groves, Vivian Pogenberg, Vlad Cojocaru, Hermann vom Bruch, Dong Han, Hannes C.A. Drexler, Marcos J. Araúzo-Bravo, Calista K.L. Ng, Ralf Jauch, Matthias Wilmanns and Hans R. Schöler – Advanced online publication in Nature Cell Biology on 03 February, 2013 – DOI:10.1038/ncb2680
Terminally differentiated cells can be reprogrammed to pluripotency by the forced expression of Oct4, Sox2, Klf4, and c-Myc1-2. 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 pluripotency3-5. 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 DNAbinding domains is structured as an -helix and exposed to the protein’s surface, in contrast to the unstructured linker of Oct1. Point mutations in this -helix alter or abolish the reprogramming activity of Oct4, but do not affect its other fundamental properties. Based on 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.
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