Computer simulations of Oct4 Binding – DNA converts cells into stem cells
Details on how an essential protein, during the conversion of regular adult human cells into stem cells, helps to activate genomic DNA, has been revealed by scientists at the Max Planck Institute in Münster and the Hubrecht Institute (KNAW — The Netherlands).
The identity of a cell is driven by which DNA is “read” or “not read” at any point in time. Through proteins called transcription factors, the signaling in the cell to start or stop reading DNA happens in the cell. As cells transition from an undesignated cell to a specific cell type, identity changes happen naturally during development. Reversing these transitions has been found to be possible. The first to push a regular skin cell back to a stem cell was Japanese researchers and they were awarded the Nobel prize in 2012.
A fuller understanding of molecular processes towards stem cell therapies
How exactly the conversion of a skin cell into a stem cell happens on a molecular scale is unknown until now. Vlad Cojocaru, the research leader at the Hubrecht Institute said, “If we want to produce such cells for individual patients in the future in a reliable and efficient manner, fully understanding the processes with atomic details is essential. To diseases like Alzheimer’s and Parkinson’s, it is believed that such engineered cell types may be part of the solution in the future, but there should more predictable and more efficient production process.”
Pioneer transcription factor
A transcription factor called Oct4 is one of the main proteins involved in stem cell generation. The activity of the gene expression of the proteins that ‘reset’ the adult cell into a stem cell is induced by this factor. In the adult cells, the genes that are induced reside in tightly packed, closed states of chromatin, and they are inactive. To allow for the expression of the genes, Oct4 contributes to the opening of chromatin. Oct4 is called as a pioneer transcription factor for this function.
Binding of Oct4 to DNA on the so-called nucleosomes was shown by Cojocaru and Jan Huertas. “In different configurations, we modeled Oct4 and the molecule has only one domain which can bind to a specific DNA sequence on the nucleosome in this phase of the process, out of its two domains. We discovered how the dynamics of nucleosomes influence Oct4 binding and which of those configurations are stable with our simulations. Our colleagues Hans Schöler in Münster and Caitlin MacCarthy performed experiments and validated our models.”
For the first time, we can see how a pioneer transcription factor binds to nucleosomes to open chromatin and regulate gene expression through computer simulations. Cojocaru says, ” Screening other transcription factors and finding out how they bind to nucleosomes can be done by using our computational approach for obtaining the Oct4 models.”
To propose a final structure for the Oct4-nucleosome complex, Cojocaru wants to refine the current Oct4 models. “By combining computer simulations with different lab experiments, we aim to obtain one final model for the binding of Oct4 to the nucleosome. We hope that our final model will provide us the opportunity to engineer pioneer transcription factors for reliable and efficient production of stem cells and other cells needed in regenerative medicine.”
