Hjörleifur Einarsson:
Regulation and impact of transcriptional variation

Date: 29-12-2021    Supervisor: Robin Andersson

All living systems show a remarkable capacity to generate robust and reproducible phenotypes despite being exposed to changes in the environment and the genetic code. One of the most striking examples of this is the development of multicellular organisms, where specific cells have to acquire certain traits and be able to respond to external cues in a cell-type specific manner all while maintaining basic cellular functions required
for cellular homeostasis.

While genetic variants have been found to affect the expression of most human genes, their effect size varies greatly, indicating the existence of regulatory mechanisms that could attenuate expression variability. At the same time, results from single cell studies suggest that high variability in expression for some genes is crucial for cell fate choices during differentiation. How these opposing mechanisms, attenuation versus
amplification of expression variability, are encoded in the genome and how they evolve remains enigmatic. The work in this thesis aims to answer this longstanding question in genetics by asking how gene expression variability is regulated and how it impacts phenotypic traits.

To this end, we performed a detailed characterization of transcription start site architecture and sequence content of promoters and their expression variability across human individuals. Our work demonstrates that expression variability is largely encoded within the promoter proximal DNA sequence and that promoter variability is reflective of distinct biological processes. Promoters showing different levels of variability are also associated with distinct transcription factor binding profiles and the complexity of these profiles is very different between stable and highly variable promoters. 

In addition, detailed transcription initiation analysis revealed a flexibility in transcription start site usage within a promoter that can attenuate promoter variability. We show that such a shift in transcription start site usage can confer transcriptional robustness in the face of genetic variation. The findings presented in this thesis favor a model in which the regulation of transcriptional noise across single cells affects specificity across cell types and variability across individuals with shared mechanisms conferring stochastic, genetic and environmental  robustness.

These findings have broad implications within the fields of genetics and transcriptomics. The fact that both robustness and plasticity of expression, in response to different sources of variation, are encoded within the local promoter sequence and architecture may help to understand how genetic variation influences phenotypic traits and diseases.