Fischer, Johanna; (2018) Chromosome Architecture of Developmental Gene Loci Rich in Conserved Non coding Elements. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

High fidelity orchestration of gene expression during development requires precise temporal and spatial control mechanisms. Distal regulatory elements function via colocalization with the promoters they regulate, resulting in the formation of specific three- dimensional conformations within the nucleus that facilitate the molecular steps required for gene activation. The current study attempts to elucidate the mechanisms of transcriptional regulation of gene expression at a particularly interesting class of developmental gene loci, which are rich in conserved non - coding elements (CNEs). Currently their role in gene regulation remains unknown. So far 35 CNE clusters have been identified, where two or more developmental genes are embedded within the cluster, which are divided via a Topologically Associated Domain (TAD) boundary. There I hypothesized that this observation could be (1) coincidence, (2) sharing functional parts of the non – coding genome and (3) co-regulation. In order to test whether the genes are co-expressed I performed a gene expression analysis in three different neuronal progenitor populations of 9 candidate loci. I observed that EphA4 and Pax3 showed evidence of co-expression in dorsal forebrain progenitors using qPCR analysis, which is a form of co-regulation. In the other candidate loci and other neuronal progenitor cell types no co-expression could be detected, however we cannot exclude that there is co-repression. Subsequently I studied the role of CNEs in gene regulation using a chromosome conformation capture approach. I used neuronal stem cells as a model. I hypothesized that either the CNEs interact to form the higher order chromatin structures, or that a single CNE preferentially interact in proximity with the promoter region to regulate gene expression. Eventually, I identified candidate CNEs, which could be regulatory elements to regulate gene expression in neuronal stem cells. Alltogether these findings may contribute to a better understanding of the orchestration of gene expression during development.

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