Sequence and Structural Determinants of Specificity Differences between Paralogous Transcription Factors

Transcription factors (TFs) control the temporal and spatial expression of target genes by interacting with DNA in a sequence-specific manner. Recent advances in high throughput experiments that measure TF-DNA interactions in vitro and in vivo have facilitated the identification of DNA binding sites for thousands of TFs. However, it remains unclear how each individual TF achieves its specificity, especially in the case of paralogous TFs that recognize distinct target genomic sites despite sharing very similar DNA binding motifs. In my work, I used a combination of high throughput in vitro protein-DNA binding assays and machine-learning algorithms to characterize and model the binding specificity of 11 paralogous TFs from 4 distinct structural families. My work proves that even very closely related paralogous TFs, with indistinguishable DNA binding motifs, oftentimes exhibit differential binding specificity for their genomic target sites, especially for sites with moderate binding affinity. Importantly, the differences I identify in vitro and through computational modeling help explain, at least in part, the differential in vivo genomic targeting by paralogous TFs. Future work will focus on in vivo factors that might also be important for specificity differences between paralogous TFs, such as DNA methylation, interactions with protein cofactors, or the chromatin environment. In this larger context, my work emphasizes the importance of intrinsic DNA binding specificity in targeting of paralogous TFs to the genome.

Dedication and Display of Portrait Statues in Hellenistic Greece: Spatial Practices and Identity Politics

This dissertation models a new approach to the study of ancient portrait statues—one that situates them in their historical, political, and spatial contexts. By bringing into conversation bodies of evidence that have traditionally been studied in discrete categories, I investigate how statue landscapes articulated and reinforced a complex set of political and social identities, how space was utilized and manipulated on a local and a regional level, and how patrons responded to the spatial pressures and visual politics of statue dedication within a constantly changing landscape.

Instead of treating sites independently, I have found it to be more productive—and, indeed, necessary—to examine broader patterns of statue dedication. I demonstrate that a regional perspective, that is, one that takes into account the role of choice and spatial preference in setting up a statue within a regional network of available display locations, can illuminate how space shaped the ancient practice of portrait dedication. This level of analysis is a new approach to the study of portrait statues and it has proved to be a productive way of thinking about how statues and context were used together to articulate identity. Understanding how individual monuments worked within these broader landscapes of portrait dedications, how statue monuments functioned within federal systems, and how monuments set up by individuals and social groups operated along side those set up by political bodies clarifies the important place of honorific statues as an expression of power and identity within the history of the site, the region, and Hellenistic Greece.