Abstract Pioneer transcription factors are proteins with a dual function. First, they regulate transcription by binding to nucleosome-free DNA regulatory elements. Second, they bind to DNA while wrapped around histone proteins in the chromatin and mediate chromatin opening. The molecular mechanisms that connect the two functions are yet to be discovered. In recent years, pioneer factors received increased attention mainly because of their crucial role in promoting cell fate transitions that could be used for regenerative therapies. For example, the three factors required to induce pluripotency in somatic cells, Oct4, Sox2, and Klf4 were classified as pioneer factors and studied extensively. With this increased attention, several structures of complexes between pioneer factors and chromatin structural units (nucleosomes) have been resolved experimentally. Furthermore, experimental and computational approaches have been designed to study two unresolved, key scientific questions: First, do pioneer factors induce directly local opening of nucleosomes and chromatin fibers upon binding? And second, how do the unstructured tails of the histones impact the structural dynamics involved in such conformational transitions? Here we review the current knowledge about transcription factor–induced nucleosome dynamics and the role of the histone tails in this process. We discuss what is needed to bridge the gap between the static views obtained from the experimental structures and the key structural dynamic events in chromatin opening. Finally, we propose that integrating nuclear magnetic resonance spectroscopy with molecular dynamics simulations is a powerful approach to studying pioneer factor–mediated dynamics of nucleosomes and perhaps small chromatin fibers using native DNA sequences. 

Structural dynamics in chromatin unraveling by pioneer transcription factors

Identification of Potential SOX2 Binding Sites to Nucleosomes via Molecular Modeling

Nucleosome-binding by TP53, TP63, and TP73 is determined by the composition, accessibility, and helical orientation of their binding sites.

Gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. To comprehensively examine TF nucleosome binding we developed Pioneer-Seq. In Pioneer-seq a library of nucleosomes containing thousands of DNA sequences with TF binding sites in all possible nucleosome orientations is bound to a TF and the protein-nucleosome complex is isolated and quantified. To demonstrate Pioneer-seq we examined nucleosome binding by OCT4, SOX2, KLF4, and c-MYC. Our results demonstrate that KLF4 and SOX2 can bind close to the nucleosome dyad with nucleosome sequence being the major factor regulating TF binding across all studied TFs.

/pdf/defining-transcription-factor-nucleosome-binding-with-2uyxgn65.pdf

Defining transcription factor nucleosome binding with Pioneer-seq

The p53 family of transcription factors plays key roles in driving development and combating cancer by regulating gene expression. TP53, TP63, and TP73—the three members of the p53 family—regulate gene expression by binding to their DNA binding sites, many of which are situated within nucleosomes. To thoroughly examine the nucleosome-binding abilities of the p53 family, we used Pioneer-seq, a technique that assesses a transcription factor’s binding affinity to its DNA binding sites at all possible positions within the nucleosome core particle. Using Pioneer-seq, we analyzed the binding affinity of TP53, TP63, and TP73 to 10 p53-family binding sites across the nucleosome core particle. We found that the affinity of TP53, TP63, and TP73 for nucleosomes was largely determined by the positioning of p53-family binding sites within nucleosomes; p53-family members bind strongly to the more accessible edges of nucleosomes but weakly to the less accessible centers of nucleosomes. We also found that the DNA-helical orientation of p53-family binding sites within nucleosomal DNA impacted the nucleosome-binding affinity of p53-family members. The composition of their binding sites also impacted each p53-family member’s nucleosome-binding affinities only when the binding site was located in an accessible location. Taken together, our results show that the accessibility, composition, and helical orientation of p53-family binding sites collectively determine the nucleosome-binding affinities of TP53, TP63, and TP73. These findings help explain the rules underlying p53-family-nucleosome binding and thus provide requisite insight into how we may better control gene-expression changes involved in development and tumor suppression.

Nucleosome-binding by TP53, TP63, and TP73 is determined by the composition, accessibility, and helical orientation of their binding sites

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Nucleosome-binding by TP53, TP63, and TP73 is determined by the composition, accessibility, and helical orientation of their binding sites.

Defining transcription factor nucleosome binding with Pioneer-seq

Nucleosome-binding by TP53, TP63, and TP73 is determined by the composition, accessibility, and helical orientation of their binding sites