Chromosome architecture of developmental gene loci rich in conserved non coding elements
2018
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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