ZURUECK HOCH VOR INHALT SUCHEN

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Proposing Institution

Max Planck Institute for Molecular Biomedicine
Project Manager

Dr. Vlad Cojocaru
Röntgenstraße 20
48149 Münster
Abstract
Transcription factors (TFs) are proteins that bind to DNA in the cell nucleus to modulate transcription. In the nucleus, DNA is packed in chromatin. The basic unit for packing is the nucleosome, composed of 147 base pairs wrapped around a protein core. This packing not only serves as a way of compacting the chromatin, but also acts as a barrier, contributing to chromatin silencing by not allowing most transcription factors to bind.However, a special class of proteins known as pioneer transcription factors are able to bind nucleosome occupied regions of DNA. It is thought that this pioneer binding opens the silenced chromatin, and allows other TFs to bind and ultimately to start transcription. Remarkably, there is no atomic resolution structural data available on how pioneer factors bind to nucleosomes. Moroever, the mechanisms by which pioneer factors contribute to chromatin opening are obscure.Interestingly, many trancription factors involved in the regulation of cellular plasticity are pioneers. In particular, Oct4, Sox2, Klf4 which are capable to reprogram adult cells to a state almost identical to the pluripotent state of embryonic stem cells have been shown to bind to closed states of chromatin by recognizing DNA wrapped in nucleosomes. In this project, we will characterize the molecular mechanism for the binding of Oct4 to nucleosomes at atomic resolution. For this, we will perform a series of classical and accelerated molecular dynamics simulations using atomic resolution models built based on experimental data available from the literature or generated by our experimental collaborators. First, we will probe different configurations of the Oct4-nucleosome complex by comparing their stability and dynamics. Then, we will characterize how nucleosome dynamics are affected by Oct4 binding. We will validate our findings in a continuous exchange with in-vitro experiments performed in already established collaborations. Our findings will contribute to the characterization of DNA recognition mechanisms by pioneer transcription factors which has numerous essential biological consequences.

Impressum, Conny Wendler