PhD defence C.C.P. (Christ) Leemans

Below is a brief summary about the dissertation:

Almost every cell in the human body contains a complete set of genetic information, stored in the form of long stretches of DNA called chromosomes. Chromatin organization packs these stretches in such a way that the code relevant to the respective cell type is more easily accessible to regulatory proteins, while the rest is packed more tightly to inhibit binding. In this thesis, work is presented that investigates how and to what extent chromatin organization influences the processes of DNA transcription and repair, using different implementations of massive parallel reporter assays (MPRAs). These assays measure transcriptional output or DNA repair outcomes from thousands to millions of comparable reporters in parallel. This massive scale is ideal for building accurate prediction models that can help elucidate the underlying relationship between chromatin organization and the processes of interest. This work produces evidence that sensitivity to differences in chromatin organization is encoded in promoter sequences independently of the strength of their transcriptional output. Furthermore, it suggests that tightly packed genomic regions known as lamina associated domains are heterogeneous in their repressive effects, as a multitude of chromatin features is predictive of the particular repressive force such regions demonstrate. Therefore, they require a more refined classification than as merely ‘repressive’, which incorporates their wide variability. Finally, in addition to their effects on transcription, chromatin organizational factors also impact DNA repair, providing input for the choice of cellular machinery used that goes beyond merely the accessibility of particular repair proteins.