Doctoral defence in Biochemistry - Sveinn Bjarnason

Doctoral candidate: Sveinn Bjarnason

Title of thesis: The structural dynamics of Sox2: Deciphering the role of intrinsically disordered regions in pioneer transcription factors

Advisor: Dr. Pétur Orri Heiðarsson, Associate Professor at the Faculty of Life and Environmental Sciences, University of Iceland

Opponents:
Dr. Sarah Shammas, Associate Professor at the University of Oxford, UK
Dr. Sebastian Deindl,  Professor at Uppsala University, Sweden

Doctoral committee:
Dr. Magnús Már Kristjánsson, Professor at the Faculty of Life and Environmental Sciences, University of Iceland
Dr. Erna Magnúsdóttir, Associate Professor at the Faculty of Medicine, University of Iceland

Chair of Ceremony:
Dr. Snæbjörn Pálsson, Professor and Head of the Faculty of Life and Environmental Sciences, University of Iceland

Abstract
The pioneer transcription factor Sox2 is well known for its crucial role in maintaining stem cell pluripotency and initiating gene expression changes critical for development and cellular reprogramming. The focus of our investigation was the role of intrinsically disordered proteins and regions in the eukaryotic nucleus with an emphasis on Sox2. Through a series of studies, we examined the dynamic interplay between Sox2, DNA, and nucleosomes. Employing advanced methodologies such as single-molecule Förster Resonance Energy Transfer and Nuclear Magnetic Resonance spectroscopy, integrated with molecular simulations, we delved into the complex changes in IDR ensembles and activation domain accessibility induced by DNA and nucleosome binding. Our findings reveal that the highly disordered C-terminal IDR of Sox2, guided by charged intramolecular interactions and Sox2’s interactions with DNA, undergoes substantial rearrangements without affecting DNA binding affinity. Furthermore, we identified a specific site within Sox2’s IDR that interacts directly with core histones, reduced rapid intrachain dynamics, and possibly influences nucleosome conformation. Using both Widom-601 and native-like nucleosome sequences, we demonstrate Sox2’s ability to remodel nucleosomes and shed light on Sox2’s capacity to displace histone H1. By unravelling the ensembles of Sox2 interacting with chromatin, our work contributes to the foundational knowledge that could lead to the development of targeted strategies to improve Sox2’s reprogramming abilities.

About the doctoral candidate
Sveinn Bjarnason was born in 1990 in Keflavík. He finished his Bachelor’s degree in Biochemistry from the University of Iceland in 2017 and his Master’s degree in 2019. Sveinn started his PhD studies in 2019 under the tutelage of Pétur Orri Heiðarsson. Sveinn is married to Dr. Sucharita Mandal.