Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Poster Abstracts

9-POS Board 9 SIMULATING THE BINDING OF PIONEER TRANSCRIPTION FACTORS TO THE NUCLEOSOME Jan Huertas 1 ; Caitlin M MacCarthy 1 ; Hans R Schöler; Vlad Cojocaru 2 ; 1 Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology , Munster, Nordrhein-Westfalen, Germany 2 Hubrecht Institute, In Silico Biomolecular Structure and Dynamics, Utrecht, The Netherlands Transcription factors are proteins that bind to DNA to regulate gene expression. In most cases, accessibility to DNA is a prerequisite for their function. However, in the nucleus the DNA is packed into chromatin, which is often inaccessible. The fundamental unit of chromatin is the nucleosome, in which 147 DNA basepairs are wrapped around a core of eight histone proteins. Interestingly, a series of transcription factors, known as pioneers, are able to bind to closed chromatin states, recognizing their binding sites even in the presence of nucleosomes. They can help open chromatin, increase DNA accessibility, and support binding of other transcription factors. For example, Oct4, a master regulator of stem cell pluripotency, is able to bind native nucleosomes in a sequence specific manner. To understand the nucleosome properties that are involved in the binding of Oct4, we performed all-atom simulations of three nucleosomes with different DNA sequences, in presence and absence of Oct4. By comparing three sequences with characteristic Oct4 binding profiles, we identified differences in dynamics and structural properties of the three nucleosomes, most of which are located in the regions known to be important for nucleosome unwrapping. We validated those findings by probing the stability of the nucleosomes in thermal unwrapping experiments. Moreover, we also characterized how the addition of Oct4 alters the dynamics of the nucleosomes, and which are the relevant nucleosome properties that explain the binding and behavior change. These findings help us understand the role of pioneer transcription factors in the binding ofclosed chromatin.

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