Pioneer transcription factors (PTFs) have the remarkable
ability
to directly bind to chromatin to stimulate vital cellular processes.
In this work, we dissect the universal binding mode of Sox PTF by
combining extensive molecular simulations and physiochemistry approaches,
along with DNA footprinting techniques. As a result, we show that
when Sox consensus DNA is located at the solvent-facing DNA strand,
Sox binds to the compact nucleosome without imposing any significant
conformational changes. We also reveal that the base-specific Sox:DNA
interactions (base reading) and Sox-induced DNA changes (shape reading)
are concurrently required for sequence-specific nucleosomal DNA recognition.
Among three different nucleosome positions located on the positive
DNA arm, a sequence-specific reading mechanism is solely satisfied
at the superhelical location 2 (SHL2). While SHL2 acts transparently
for solvent-facing Sox binding, among the other two positions, SHL4
permits only shape reading. The final position, SHL0 (dyad), on the
other hand, allows no reading mechanism. These findings demonstrate
that Sox-based nucleosome recognition is essentially guided by intrinsic
nucleosome properties, permitting varying degrees of DNA recognition.