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This study reveals how transcription factors Sox2 and Oct4 can bind to DNA sequences outside their typical recognition sites when operating on nucleosome-wrapped chromatin. The researchers found that protein-protein interactions between transcription factors enable them to recognize non-canonical DNA sequences by bridging across DNA loops on the nucleosome surface, and that Sox2 can displace parts of Oct4 while maintaining contact through its disordered regions. These mechanisms expand the range of DNA sites where pioneer transcription factors can bind and function in gene regulation.
Why it matters
Understanding how transcription factors gain access to chromatin at non-standard binding sites has important implications for decoding gene regulatory networks during development and disease. These findings could inform strategies for cellular reprogramming and regenerative medicine where precise control of transcription factor activity is essential.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Recruitment of transcription factors (TFs) to non-cognate DNA sequences is widely observed, but the underlying mechanisms remain poorly understood. Here, we show that, within the nucleosome, Sox2 can bind an Oct4 motif, interact with the Oct4 POU-specific domain, and displace the Oct4 homeodomain. We also observe Sox2 binding at multiple near-canonical and non-canonical DNA sites, with these interactions promoted by a second Sox2 molecule or by nearby nucleosome-bound Oct4. The TF-TF interactions can bridge across DNA gyres, bringing together binding sites that are distant in linear DNA but spatially proximal on the nucleosome. We further find that Sox2 can engage across nucleosomal DNA gyres through loop regions and/or intrinsically disordered segments, providing an additional mode of chromatin binding. Together, our structural and biochemical data reveal how TF-TF interactions change DNA recognition on the nucleosome, enabling binding to non-cognate sequences and expanding the repertoire of pioneer factor interactions on chromatin.
Source: Transcription factor interactions promote binding to non-cognate DNA sites