PhD defense: Maria Dalby
Regulation and maintenance of transcriptional specificity
Supervisor: Postdoc Robin Andersson, Computational and RNA Biology
Prof. Wyeth Wasserman, BC Children's Hospital Research Institute, University of British Columbia
Prof. Susanne Mandrup, University of Southern Denmark
Prof. Albin Sandelin, University of Copenhagen
Cell-type specific control of metazoan gene expression is mediated by events at gene promoters and gene-distal transcriptional enhancers. The correct spatio-temporal activities of these transcriptional regulatory elements (TREs) are therefore essential for organismal development and tissue homeostasis. Despite their essential roles in gene regulation, the exact mechanisms by which TREs achieve correct transcriptional activities in a given cell, are not well understood.
The work done as part of this thesis has aimed to further our understanding of the properties of TREs and the determinants of enhancer and promoter functions. The work is based on computational analyses and modelling of transcriptional regulatory activities based on sequencing data, in particular, 5’ end RNA- and ChIP-sequencing data. At the TRE-level, all three projects included in this thesis, have centred around enhancer transcription.
To investigate the link between promoter activity and enhancer function across Metazoa, we present a systematic transcriptome characterization in Drosophila melanogaster, showing that the majority of active enhancers and gene promoters are divergently transcribed. This work brings forward a unified promoter architecture of TREs that is conserved across Metazoa, and whose regulatory functions are related to the strengths of their core promoter elements.
Using inferred enhancer and promoter activity from transcription initiation data, we investigate how TRE components relate to age-associated neurological diseases. We demonstrate major TRE dynamics across the aging brain and connect these changes to transcription regulation and alterations in cell type proportions. The work further suggests that aging-associated transcriptional changes are linked to neuroinflammation and degenerative disease in the human cerebral frontal lobe.
Bringing TRE activities into a larger integrative study, we relate transcription and genome architectures to biases in histone modification inheritance during DNA replication. This work demonstrates that parental histones H3-H4 are recycled to both daughter DNA strands with a leading strand bias. In general, the epigenetic chromatin state is propagated with high fidelity through DNA replication, yet this work proposes a window of opportunity for alterations in the chromatin landscape with importance for cell fate determination.