In Silico Biomolecular Structure and Dynamics

Vlad Cojacaru

Our Research

We use computational approaches to understand the structure and dynamics of biomolecules at or near atomic resolution, with a special focus on biomolecular recognition. In particular, we are interested in how a special class of proteins known as transcription factors explore DNA to recognize their binding sites, a process crucial for establishing gene regulation programs that confer a specific identity to a given cell.

DNA recognition in nucleosome free regions
Transcription factors are proteins that recognize specific DNA elements in the genome to establish gene regulation programs. Many of them are involved in defining the identity of the cell. Moreover, some transcription factors can be induced to change the fate of a cell. For example, four transcription factors are sufficient to convert a somatic cell to a pluripotent cell, very closely resembling an embryonic stem cell. This process, known as cellular reprogramming has important implications for regenerative medical applications. Among these four factors, Oct4, a member of the POU family binds cooperatively with different members of the Sox family to composite motifs with varying spacers between the individual binding sites. In recent years, we have elucidated the structural features and dynamics that modulate the cooperativity of Oct4 with Sox2 in pluripotent cells and with Sox17 in primitive endoderm cells (Figure 1). Based on these findings, we predicted and validated mutations that modify the function of the Sox factors. Currently, we are aiming to understand different mechanisms by which transcription factors use multiple DNA binding domains and DNA binding cooperativity to recognize DNA to establish multiple layers of specificity required for the tight regulation of gene expression.

DNA recognition in nucleosome occupied regions
The nucleosome is the structural unit of chromatin in the cell nucleus, wrapping 148 base pairs of DNA around eight histone proteins. In closed chromatin states, an additional histone protein known as linker histone contributes to DNA compaction. We have shed new light on the mechanisms by which the linker histone binds to the nucleosome core particle (Figure 2). Some of the transcription factors involved in cell fate transitions bind to closed chromatin states recognizing DNA while it is wrapped in nucleosomes. These factors are known as pioneer transcription factors. The structural features and dynamics that module nucleosome recognition by pioneer transcription factors are not understood. Moreover, there is no experimentally-determined structure available of a pioneer factor bound to the nucleosome. Therefore, we are aiming to characterize the binding of selected pioneer factors to nucleosomes.

Research Group

Vlad Cojacaru
Group name: Cojacaru group
Research field: In Silico Biomolecular Structure and Dynamics
Department: Hubrecht Institute

Contact

Uppsalalaan 8
3584 CT
Utrecht
Office:
Building:
v.cojocaru@hubrecht.eu
https://www.hubrecht.eu/research-groups/cojocaru-group/