Image-based high-content screens (HCS) hold tremendous promise for cell-based
phenotypic screens. Challenges related to HCS include not only storage and
management of data, but critical analysis of the complex image-based data. I
implemented a data storage and screen management framework and developed
approaches for data analysis of a number high-content microscopy screen formats.
I visualized and analysed pilot screens to develop a robust multi-parametric assay
for the identification of genes involved in DNA damage repair in HeLa cells.
Further, I developed and implemented new approaches for image processing and
screen data normalization. My analyses revealed that the ubiquitin ligase RNF8
plays a central role in DNA-damage response and that a related ubiquitin ligase
RNF168 causes the cellular and developmental phenotypes characteristic for the
RIDDLE syndrome. My approaches also uncovered a role for the MMS22LTONSL
complex in DSB repair and its role in the recombination-dependent repair
of stalled or collapsed replication forks.
The discovery of novel bioactive molecules is a challenge because the fraction of active
candidate molecules is usually small and confounded by noise in experimental
readouts. Cheminformatics can improve robustness of chemical high-throughput
screens and functional genomics data sets by taking structure-activity relationships
into account. I applied statistics, machine learning and cheminformatics
to different data sets to discern novel bioactive compounds. I showed that phenothiazines
and apomorphines are regulators for cell differentiation in murine
embryonic stem cells. Further, I pioneered computational methods for the identification of structural features that influence the degradation and retention of
compounds in the nematode C. elegans. I used chemoinformatics to assemble a
comprehensive screening library of previously approved drugs for redeployment
in new bioassays. A combination of chemical genetic interactions, cheminformatics
and machine learning allowed me to predict novel synergistic antifungal small
molecule combinations from sensitized screens with the drug library. In another
study on the biological effects of commonly prescribed psychoactive compounds,
I discovered a strong link between lipophilicity and bioactivity of compounds in
yeast and unexpected off-target effects that could account for unwanted side effects
in humans. I also investigated structure-activity relationships and assessed
the chemical diversity of a compound collection that was used to probe chemical-genetic
interactions in yeast. Finally, I have made these methods and tools available
to the scientific community, including an open source software package called
MolClass that allows researchers to make predictions about bioactivity of small
molecules based on their chemical structure
