The figure represents Huertas’ work and was featured on the cover of the May 2020 issue of the Biophysical Journal. 1 microsecond from the life time of a nucleosome is shown by superposition of structures taken at different time points from a computer simulation. DNA is in orange and the histone proteins that wrap DNA are in green. In the insert, the Oct4 protein bound to the nucleosome is shown in light blue. The background (image credit, Juan Gärtner, iStock images) shows molecules in the cell nucleus and represents the genomic background of the nucleosome. 30 April 2021 Thesis defense Jan Huertas: “Structural dynamics of Nucleosomes bound by the Pioneer Transcription Factor Oct4” Back to news Jan Huertas, from the group of Vlad Cojocaru, successfully defended his thesis “Structural dynamics of Nucleosomes bound by the Pioneer Transcription Factor Oct4” on the 22nd of April at the University of Münster in Germany. In his doctoral studies, Huertas took advantage of the “computational nanoscope”. Using computer simulation algorithms, this technology visualizes molecules in motion to investigate how proteins recognize wrapped genomic DNA. In particular, he revealed how an essential protein for the conversion of skin cells to pluripotent stem cells unravels nucleosomes. Computational nanoscope Active molecules in our cells can be visualized in motion at very high (atomic) resolution using computer simulations. These methods have become so accurate in recent years that researchers in the field consider them as a “computational nanoscope”. Observing the molecules moving on the computer is similar to observing them under a very high resolution nanoscope. The applications of the computational nanoscope range from studying the folding of individual proteins to the dynamics of entire gene locations in the genome. Conversion of adult cells into stem cells Only four proteins known as transcription factors are required to convert adult skin cells, also called somatic cells, into cells that are almost identical to embryonic pluripotent stem cells. These embryonic pluripotent stem cells have the ability to become any cell type present in the body. For this discovery, the 2012 Nobel Prize in Physiology and Medicine was awarded. How these four proteins achieve such a major cellular transition is still not understood. In recent years, it has been proposed that when introduced in somatic cells, these proteins provoke the unpacking of DNA in direct or indict ways. For this function, these proteins have been named Pioneer Transcription Factors. In the genome, nucleosomes form the basic structural units that wrap DNA. However, it is still largely unknown how the transcription factors bind to DNA in that context. The figure represents Huertas’ work and was featured on the cover of the May 2020 issue of the Biophysical Journal. 1 microsecond from the life time of a nucleosome is shown by superposition of structures taken at different time points from a computer simulation. DNA is in orange and the histone proteins that wrap DNA are in green. In the insert, the Oct4 protein bound to the nucleosome is shown in light blue. The background (image credit, Juan Gärtner, iStock images) shows molecules in the cell nucleus and represents the genomic background of the nucleosome. Oct4 as Pioneer Transcription Factor Oct4 is one of these Pioneer Transcription Factors. It is a protein that is expressed only early in embryonic development and in germ cells in adults. When introduced in adult cells, together with at least two other factors, it converts the cells into stem cells. In his thesis, Huertas describes how Oct4 binds to nucleosomes and how it requires the flexibility of nucleosomes to bind. Additionally, he describes how Oct4 in some cases provokes large scale opening of nucleosomes. Huertas’ findings have general implications for understanding how Pioneer Transcription Factors provoke the opening of chromatin – the structure that packs DNA in the cells. Such opening is required for converting cells from one type to another. Jan Huertas is captivated by the organization of the DNA in cell and the mechanism by which that changes during cellular transitions. His plans for the near future are to continue in his academic career as a postdoctoral researcher. Ideally, his future project will be dedicated to understanding the dynamics of chromatin structure and how this is changed by other factors at a higher level.
