thesis published Roshan Prizak author 4456104E-F248-11E8-B48F-1D18A9856A87 Gašper Tkačik supervisor GaTk department NiBa department Biophysics of information processing in gene regulation project Transcription factors, by binding to specific sequences on the DNA, control the precise spatio-temporal expression of genes inside a cell. However, this specificity is limited, leading to frequent incorrect binding of transcription factors that might have deleterious consequences on the cell. By constructing a biophysical model of TF-DNA binding in the context of gene regulation, I will first explore how regulatory constraints can strongly shape the distribution of a population in sequence space. Then, by directly linking this to a picture of multiple types of transcription factors performing their functions simultaneously inside the cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions between transcription factors and binding sites that lead to erroneous regulatory states -- and understand the constraints this places on the design of regulatory systems. I will then develop a generic theoretical framework to investigate the coevolution of multiple transcription factors and multiple binding sites, in the context of a gene regulatory network that performs a certain function. As a particular tractable version of this problem, I will consider the evolution of two transcription factors when they transmit upstream signals to downstream target genes. Specifically, I will describe the evolutionary steady states and the evolutionary pathways involved, along with their timescales, of a system that initially undergoes a transcription factor duplication event. To connect this important theoretical model to the prominent biological event of transcription factor duplication giving rise to paralogous families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription factors, a major family in humans, and focus on the patterns of evolution that paralogs have undergone in their various protein domains in the recent past. https://research-explorer.ista.ac.at/download/6071/6072/Thesis_final_PDFA_RoshanPrizak.pdf application/pdfno https://research-explorer.ista.ac.at/download/6071/6073/thesis_v2_merge.zip application/zip Institute of Science and Technology Austria2019 eng 2663-337X10.15479/at:ista:th6071 189 https://research-explorer.ista.ac.at/record/955 https://research-explorer.ista.ac.at/record/1358 R. Prizak, Coevolution of Transcription Factors and Their Binding Sites in Sequence Space, Institute of Science and Technology Austria, 2019. Prizak, R. (2019). <i>Coevolution of transcription factors and their binding sites in sequence space</i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/at:ista:th6071">https://doi.org/10.15479/at:ista:th6071</a> Prizak R. 2019. Coevolution of transcription factors and their binding sites in sequence space. Institute of Science and Technology Austria. R. Prizak, “Coevolution of transcription factors and their binding sites in sequence space,” Institute of Science and Technology Austria, 2019. Prizak R. Coevolution of transcription factors and their binding sites in sequence space. 2019. doi:<a href="https://doi.org/10.15479/at:ista:th6071">10.15479/at:ista:th6071</a> Prizak, Roshan. <i>Coevolution of Transcription Factors and Their Binding Sites in Sequence Space</i>. Institute of Science and Technology Austria, 2019, doi:<a href="https://doi.org/10.15479/at:ista:th6071">10.15479/at:ista:th6071</a>. Prizak, Roshan. “Coevolution of Transcription Factors and Their Binding Sites in Sequence Space.” Institute of Science and Technology Austria, 2019. <a href="https://doi.org/10.15479/at:ista:th6071">https://doi.org/10.15479/at:ista:th6071</a>. 60712019-03-06T16:16:10Z2026-04-08T13:54:25Z