Oct4 interprets and enhances nucleosome dynamics.

Abstract

Transcription factors are proteins that bind to DNA to regulate gene expression. Historically, DNA accessibility has been considered a prerequisite indispensable for transcription factor function. Nevertheless, in recent years certain transcription factors have been shown to have “pioneering activity”, meaning that they can bind their specific binding sites in packed regions of the genome, where the DNA is wrapped around a nucleoprotein complex called the nucleosome. Oct4 is a pioneer transcription factor, involved in pluripotency maintenance and that can be used for reprogramming of adult cells into stem-cell like cells. Using experimental data, we built models of Oct4 bound to two different native nucleosomes. We then performed over 50 µs of atomistic simulations of the Oct4-nucleosome complexes, which we compared to our already existing library of 25 µs of nucleosome alone simulations. We found that nucleosome flexibility is a requirement for a multidomain transcription factor like Oct4 to bind. Furthermore, we described two different mechanisms in which Oct4 can alter nucleosome dynamics, either by stabilizing naturally occurring nucleosome opening events or inducing large opening events not seen in the nucleosome alone simulations. The atomistic resolution allowed us to observe an interplay between the histone tails and the two DNA binding domains of Oct4 for the opening events to occur. Overall, our findings provide a mechanistic description of the effects of a pioneer transcription factor bound to a nucleosome, at an unprecedented resolution. This work allows us to begin understanding the changes of genome architecture that happen upon expression and binding of certain transcription factors, and ultimately gives us the tools to understand cell-fate transitions.