A key protein for converting adult stem cells into cells that resemble embryonic stem cells has been visualized in unprecedented detail by an international team of researchers. By combing experiments and computer simulations, the team visualized how the Oct4 protein binds and opens short pieces of DNA while wrapped around nuclear storage proteins (histones), just like in our genome. The team was lead by two researchers from the Max Planck Institute for Molecular Biomedicine in Münster: Hans Schöler and Vlad Cojocaru (now at Babeş-Bolyai University of Cluj-Napoca in Romania and Utrecht University in The Netherlands).
Native genomic nucleosomes bound (dark blue) by Oct4 (red) and in free form (yellow). The surfaces and ribbons illustrate the DNA and the core structured regions of the histones respectively. Oct4 stabilizes a partially open form of one nucleosome (on the right) and induces a large opening in the other (on the left). Oct4’s impact on the structures of these nucleosomes depends on the mobility of the flexible histone tails (gray and light blue in free and Oct4-bound nucleosomes respectively) and of its two subdomains (red) that bind to different faces of DNA. The background shows colonies of human induced pluripotent cells cultured on feeder cells (lower left corner) and derived from human skin cells by the induction of the indispensable Oct4 and three other proteins.
Adult cells can be converted into embryonic stem cell-like cells (induced pluripotent cells, iPSCs) using a cocktail of just four proteins. In recent years, this cellular reprogramming technology has contributed immensely to disease modelling, drug development, and cell replacement therapies. However, many questions about the molecular mechanisms of this conversion remain unanswered. For example, one essential step is the opening of DNA in the cells to be converted. Each of our cells contains about two meters of DNA packed in a structure known as chromatin. In chromatin, the DNA is tightly wrapped around histones in repeating structural units known as nucleosomes. So, how do these four proteins open the DNA when expressed in adult cells?