Impact of Nucleosome Positioning in Promoters on Transcription Regulation for Selection of Expression Activating Transcription Factor Binding Sites

by Niels Benjamin Paul
Cumulative thesis
Date of Examination:2024-10-21
Date of issue:2025-10-16
Advisor:Prof. Dr. Tim Beißbarth
Referee:Prof. Dr. Tim Beißbarth
Referee:Prof. Dr. Karl Toischer
Persistent Address: http://dx.doi.org/10.53846/goediss-11569

 

 

Files in this item

Name:Thesis_NielsPaul.pdf
Size:5.66Mb
Format:PDF
Description:Thesis

The following license files are associated with this item:

Abstract

English

Gene regulation processes are crucial for development and the adaptation of cells, tissues or whole organisms to changing environments. Nucleosome positioning in promoter regions is of pivotal importance in gene regulation, since it controls DNA-motif accessibility via steric hinderance and thereby alters the set of transcription factors that can influence a gene’s expression. Identifying key transcription factors that regulate expression bares the potential to pinpoint the changes in the environment causative for the observed changes. The presented work employs a classifier that predicts nucleosome occupancy from DNA sequence, thereby elucidating the role of sequence information as a key determinant of the positioning of regulatory nucleosomes in promoters. The function of nucleosome positioning in gene activation was further substantiated by the development of an algorithm for the prediction of gene expression based on histone modification patterns surrounding the transcription start site. The algorithmic structure comprises an innovative combination of an optimisation algorithm for feature extraction and a gradient tree boosting algorithm for subsequent classification. This combination outperformed previous algorithms while maintaining the explainability of individual decisions. The generalisation of the algorithm across different samples revealed that the usage of histone modifications for gene regulation is celltype and tissue independent. The implications of nucleosome positioning for the regulatory landscape were further analysed using data from a multimodal single-nuclei experiment. The integration of paired chromatin accessibility and transcriptome data at the cellular level demonstrated that nucleosome positioning considerably restricts the number of potentially relevant DNA binding sites. These findings form the basis of an integrative master-regulator analysis, which aims to identify causative triggers for expression changes in the context of specific phenotypes.
Keywords: Nucleosome positioning; Gene regulation; Gene expression; Expression prediciton
Schlagwörter: Gene expression; Gene regulation; Nucleosome positioning; Expression prediction
 
Statistik