Understanding protein-DNA binding events

Kiesel, Anja Sophie (2017): Understanding protein-DNA binding events. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

Abstract

DNA binding proteins regulate essential biological processes such as DNA replication, transcription, repair, and splicing. Transcription factors (TFs) are in the focus of this work because they have the largest effect of activating and repressing gene expression by influencing transcription rates. It is important to model TF binding affinity to DNA and to predict protein-DNA binding events to understand how they regulate cell mechanisms. Higher order Markov models bring \textit{de-novo} motif discovery to the next level. BaMM!motif has been shown to provide robust predictions of these more sophisticated binding models. Here I introduce the BaMM!motif web application, a web-based platform which combines \textit{de-novo} motif discovery with motif enrichment and motif-motif comparison tools and a database of known motifs. This web application enables the usage of the BaMM!motif algorithm in a straightforward and robust environment. Post-translational histone modifications and linker histone incorporation regulate chromatin structure and genome activity. How these systems interface on a molecular level is unclear. Using biochemistry, one observes that the modification behavior of N-terminal histone H3 tails depends on the nucleosomal contexts. I found that linker histones inhibit modifications of different H3 sites on a genome-wide level.This proposes that alterations of H3 tail-linker DNA interactions by linker histones execute basal control mechanisms of chromatin function. Pervasive transcription of eukaryotic genomes stems to a large extent from bidirectional promoters that synthesize mRNA and divergent noncoding RNA (ncRNA). Here, I show that early termination that relies on the essential RNA-binding factor Nrd1 attenuates transcription of 32 genes in yeast. Further, depletion of Nrd1 from the nucleus results in 1,526 Nrd1-unterminated transcripts (NUTs) that originate from nucleosome-depleted regions (NDRs) and can deregulate mRNA synthesis by antisense repression and transcription interference.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Protein-DNA binding motif discoverywebserver, histone modification linker, histone nrd1 promoter proximal termination
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 30. November 2017
• 1. Referee: Söding, Johannes
• Signature of the printed copy: 0001/UMC 25117