Simulações em computador visualizam como o DNA converte células em células-tronco

segunda-feira, fevereiro 17, 2020

Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

Jan Huertas, Caitlin M. MacCarthy, Hans R. Schöler, Vlad Cojocaru

Open Access Published: January 16, 2020



An illustration showing a stem cell giving rise to more stem cells or specialised cells.

Abstract

Transcription factor (TF) proteins bind to DNA to regulate gene expression. Normally, accessibility to DNA is required for their function. However, in the nucleus, the DNA is often inaccessible, wrapped around histone proteins in nucleosomes forming the chromatin. Pioneer TFs are thought to induce chromatin opening by recognizing their DNA binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds to DNA in nucleosomes in a sequence-specific manner. Here, we reveal the structural dynamics of nucleosomes that mediate Oct4 binding from molecular dynamics simulations. Nucleosome flexibility and the amplitude of nucleosome motions such as breathing and twisting are enhanced in nucleosomes with multiple TF binding sites. Moreover, the regions around the binding sites display higher local structural flexibility. Probing different structures of Oct4-nucleosome complexes, we show that alternative configurations in which Oct4 recognizes partial binding sites display stable TF-DNA interactions similar to those observed in complexes with free DNA and compatible with the DNA curvature and DNA-histone interactions. Therefore, we propose a structural basis for nucleosome recognition by a pioneer TF that is essential for understanding how chromatin is unraveled during cell fate conversions.

Significance

Pioneer transcription factors (TFs) are proteins that bind to DNA in closed chromatin and mediate chromatin opening during cell fate conversions. In closed chromatin, the DNA is wrapped around histone proteins in nucleosomes, which partially occlude the DNA features required for protein binding. Nevertheless, how pioneer factors recognize DNA on nucleosomes remains unknown. Here, we describe how structural dynamics mediate the binding of Oct4, a pioneer TF, to the nucleosome and propose a structural basis for the Oct4-nucleosome interaction. Our findings reveal how pioneers such as Oct4 are able to engage wrapped DNA. Moreover, we demonstrate that molecular simulations can be used as a tool to screen for configurations of TFs that are compatible with nucleosome binding.

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