title: Deciphering transcriptional regulation in cancer cells and development of a new method to identify key transcriptional regulators and their target genes
creator: Bauer, Tobias Hartmut
subject: ddc-570
subject: 570 Life sciences
description: Cancer cells accumulate genetic changes during carcinogenesis. The dimension of these changes range from point mutations to large chromosomal aberrations. It has been widely accepted that essential genetic programs are thereby dysregulated that normally would prevent uncontrolled cellular division and growth. Transcription factors (TFs) are key proteins of gene regulation and are frequently associated with genetic pathologies, e.g. MYCN in neuroblastomas (NBs). Research on gene regulation -in general or condition-specific- thus is a central aspect in cancer research, and it is also the focus of my work. In a carcinogenesis model of NBs without MYCN-amplification, mutations of chromosome 11q (11q-CNA) are suspected to critically influence tumor development. We were able to refine this model by means of gene expression analysis on 11q-CNA in NBs with different clinical outcome. Gene expression profiles of NBs with unfavorable progression differed significantly between tumors with and without 11q-CNA, whereas 11q-CNA in NBs with favorable outcome is apparently compensated by a yet unknown mechanism. The TF-encoding gene CAMTA1 is located on the chromosomal region 1p, which is frequently deleted in NBs. In vitro experiments with ectopic induction of CAMTA1 yielded CAMTA1-regulated genes with different gene expression profiles that were functionally associated by enrichment analyses with cell cycle regulation and neuronal differentiation. The suggested role of CAMTA1 as a tumor suppressor gene was confirmed by additional in vivo experiments. Furthermore, we studied the effect of MYC and MYCN in NBs without MYCN-amplification and found that these TF also strongly regulate a large number of common target genes according to their own gene expression in these tumors. Promoter analyses and chromatin immunoprecipitation additionally supported the regulation of the determined target genes by MYC/MYCN. The genome-wide application of promoter and enrichment analyses on gene expression data from mouse models enabled us to predict target TFs of Rage signaling. E2f1 and E2f4 were validated experimentally as components of the Rage-dependent gene regulatory network. Finally, we used our experience from gene expression analysis to develop a novel machine learning method to precisely predict TF target gene relationships in human. We combined results from a genome-wide correlation meta-analysis on 4064 microarray gene expression profiles and promoter analyses on TF binding sites with known regulatory interactions between TFs and target genes in our approach. Our method outperformed other comparable methods in human, as we improved shortcomings of other algorithms specifically for higher eukaryotes, in particular the frequently (erroneously) assumed correlation between the mRNA expression of TFs and their target genes. We made our method freely available as a software package with multiple applications like the identification of key TFs in a multiplicity of cellular systems (e.g. cancer cells).
date: 2011
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/12499/1/Dissertation_Tobias_Bauer.pdf
identifier: DOI:10.11588/heidok.00012499
identifier: urn:nbn:de:bsz:16-opus-124992
identifier:   Bauer, Tobias Hartmut  (2011) Deciphering transcriptional regulation in cancer cells and development of a new method to identify key transcriptional regulators and their target genes.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/12499/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng