For the cover of the May 5 issue of Biophysical Journal, we imagined an illustration that presents the two most important discoveries from our study: the structural flexibility of a genomic nucleosome with multiple transcription factor binding sites, and a representative structural model of the transcription factor–nucleosome complex we studied. Additionally, to put our findings in the context of the special issue, “Multiscale Modeling of Chromatin: Bridging Experiment with Theory,” we layered in a background image depicting the genomic environment where the interaction between transcription factors and nucleosomes occurs.
While many transcription factors primarily bind naked DNA, a special group known as pioneer factors can bind DNA wrapped around histone proteins in nucleosomes. Pioneer factors are particularly important for cell fate conversions. The essential regulator of pluripotency Oct4 is a pioneer factor, which interacts with nucleosomes during the conversion of adult, somatic cells into pluripotent stem cells. We focused on one particular nucleosome bound by Oct4 and other transcription factors, which we found to have increased structural flexibility compared to other nucleosomes. To express this finding, we represented the complete range of breathing motions of the genomic nucleosome in one composite image. We composed the image by rendering multiple snapshots from our three-microseconds-long molecular dynamics simulations of this nucleosome. We show all of these simultaneously on a frame with this nucleosome rendered in cartoon representation.
While probing the stability of Oct4-nucleosome complexes in molecular dynamics simulations, we found that alternative configurations in which Oct4 binds to partial binding sites with one of its two domains are compatible with the DNA curvature and histone-DNA contacts in the nucleosome. To express this finding, we rendered one representative binding mode of Oct4 to the nucleosome and we show it as an insert pointing away from the location of the Oct4 binding site, with the residues relevant for the protein-DNA interaction highlighted. This and the other structural models of Oct4-nucleosome complexes we present in our study were built based on genomic data available for Oct4 binding and nucleosome positioning. After our study was published, the first experimental structures of Oct4 and its partner in embryonic stem cells Sox2 bound to nucleosomes were reported (Michael et al. 2020, Science, doi: 10.1126/science.abb0074 and Dodonova et al. 2020, Nature, doi: 10.1038/s41586-020-2195-y), revealing further exciting features of the interactions between transcription factors and nucleosomes.
- Jan Huertas, Caitlin MacCarthy, Hans Schöler, and Vlad Cojocaru