Evgenia Nikolova, PhD
Assistant Research Professor
Department of Biophysics
Johns Hopkins University
Host: Dr. Michael Buck
Seminar TItle: Role of structural plasticity in pioneer factor-nucleosome interactions
Abstract: Pioneer transcription factors can bind directly to nucleosomal DNA and promote regulatory events, leading to gene activation. We use high-resolution nuclear magnetic resonance (NMR) spectroscopy combined with biochemistry and computation to study how two key pioneer factors and functional partners, Sox2 and Oct4, interact with nucleosomes. We find that the conformation and affinity of Sox2 for nucleosome sites depend strongly on their position, DNA sequence as well as on nucleosome dynamics. Sox2, which is partially disordered in the free state but becomes structured upon DNA binding and bending, forms a super-stable DNA-like nucleosome complex at superhelical location 5, where histone-DNA interactions are weaker. However, at suboptimal sites where DNA may be harder to deform, Sox2 favors more dynamic states linked to reduced DNA bending. Mutational studies reveal that such impaired Sox2 structure is coupled to reduced DNA bending and synergism between Sox2 and Oct4. At the same time, installing destabilizing histone mutants or variants, which increase the dynamics of nucleosomal DNA and histone tails, can enhance Sox2 and Oct4 association. Overall, our findings fit a model where, together, the structural plasticity of Sox2, nucleosomal DNA and histones dictate how this pioneer factor engages with nucleosomes and cooperates with other proteins. This study could shed light on how pioneer factors select their sites in the genome and alter chromatin structure.
Sara Thomas
Email: msthomas@buffalo.edu