Prof. Dr. Axel Imhof

Project Title: Adenovirus Chromatin Dynamics and Gene Expression

Project description:

Adenoviruses (AdV) are highly efficient human pathogens used extensively as therapeutic
vectors, notably in vaccination. While their efficiency in delivering and expressing a genome
is empirically proven, the underlying molecular mechanisms—particularly concerning how
the viral DNA is managed within the host nucleus—remain poorly understood. The overall
goal of this project is to precisely characterize the molecular, morphological, and mechanistic
context governing adenoviral gene expression to fully elucidate this efficiency.
To achieve this, we will focus on the dramatic epigenetic remodeling the viral genome
undergoes upon nuclear entry. Earlier work showed that the viral pVII protein is partially
replaced by host histones at the onset of transcription. We will significantly expand these
findings by characterizing the global proteome bound to viral DNA in a time-resolved
manner throughout the virus’s entire life cycle, utilizing the immunologically competent
HFF-CAR system.
These comprehensive measurements will allow us to define the early steps of nuclear
delivery and transcription, including the identity of the molecular chaperones mediating the
exchange of pVII for host histones. Crucially, we will comprehensively study the deposition
of host histone variants and their modifications onto the nuclear viral genome before
replication. This process is unique, allowing us to compare modification dynamics on the
viral DNA to those measured on newly synthesized host DNA and during repair. Finally, we
will employ proximity biotinylation to map the proteomic neighborhood of the viral
chromatin throughout its lifespan, revealing unknown pathways that regulate infection and
virus replication.

Potential supervisors: Hua Jie 

Must have skills:

• A general idea and ideally hands-on experience with mass spectrometry or with analysis of large data sets
• At least 3 months of hands-on experience in a molecular biology lab
• General knowledge of how to write and use R-scripts