Pioneer factors steer chromatin remodeling for gene accessibility

DNA inside cells is wrapped around histone proteins to form repeating units called nucleosomes. Many nucleosomes assemble into chromatin, the tightly packed form of DNA that organizes the genome into chromosomes. This packaging helps control which genes are accessible, and which remain silent.

When genes need to be activated, chromatin structure must be adjusted locally. This typically involves transcription factors that bind regulatory DNA sequences and work together with chromatin remodeling complexes to reposition nucleosomes.

Most transcription factors struggle to bind nucleosome-wrapped DNA, except for one class of transcriptions factors: the pioneer transcription factors. Two members, OCT4 and SOX2, often bind together as a pair.

OCT4-SOX2 recruit the BAF chromatin remodeling complex, one of the major human remodelers and a complex frequently mutated in cancer. But this raises a question: If OCT4-SOX2 bind DNA within a nucleosome and BAF needs to reposition that same nucleosome, how do they operate on the same piece of DNA without interfering with each other?

A team led by Nicolas Thomä at EPFL’s Institute for Cancer Research (ISREC) set out to answer this question. Their findings, published in Molecular Cell, reveal a dynamic interplay between OCT4-SOX2 and BAF that fine-tunes how chromatin is opened around key regulatory DNA elements.

Using biochemical remodeling assays, single-molecule fluorescence experiments, and cryo-electron microscopy, the researchers tracked how BAF moves nucleosomes and how this motion changes in the presence of OCT4-SOX2.

They found that BAF does not simply slide nucleosomes in one direction. Instead, it frequently reverses course while remaining attached, producing a back-and-forth movement that dynamically repositions nucleosomes.

When OCT4-SOX2 are bound to DNA, this movement becomes biased. Nucleosomes are less likely to move toward the transcription factor binding site and more likely to move away from it.

Cryo-electron microscopy structures explain why. BAF can engage an OCT4-SOX2-bound nucleosome in two opposite orientations. In one orientation, continued movement would be expected to bring the remodeler into conflict with the bound transcription factors. In the other, BAF positions itself so that nucleosome movement proceeds away from them.

The structures also capture intermediate conformations of the remodeler, including an ADP-bound state that may facilitate switching between orientations.

Together, the results show that pioneer transcription factors do not simply wait for chromatin to open. They influence how remodelers act, steering nucleosome movement in ways that help preserve access to key regulatory DNA sites. This coordinated behavior provides a clearer picture of how gene activation is controlled during development and how disruptions in chromatin remodeling may contribute to disease.

Other contributors

• Friedrich Miescher Institute for Biomedical Research
• University of Basel
• Uppsala University
• Swiss Institute of Bioinformatics