PhD defence H.B. (Hedda) Somsen

Below is a brief summary of the dissertation: 

Neurodevelopment requires specific gene expression patterns to allow correct spatiotemporal cell type generation. This complex process is therefore highly sensitive and changes in developmental gene expression can result in neurodevelopmental disorders (NDDs). Understanding the mechanistic cause for many NDD’s pathogenic phenotypes remains challenging. Although patients present large genotypic heterogeneity, clinical overlap can be observed, indicating a similar pathogenic mechanism. We identify a large clinical overlap between NDDs caused by genetic variants in genes coding for transcription pausing regulators and hypothesize this to be the cause for NDDs such as Cornelia de Lange syndrome. In this thesis, we study misregulation of transcription as a possible cause for these NDDs by focusing on three such proteins: Integrator complex subunit 8 (INTS8), NIPBL and BRD4. To allow representative in vitro studies, we use human pluripotent stem cells to generate various 2D and 3D, heterogeneous and homogeneous neural cultures. A multi-omics approach is then used to asses the effects of patient variants on protein function, transcription regulation and subsequent effect on the transcriptome.