All genetic information required for the development and functioning of an organism is stored in billions of base pairs of deoxyribonucleic acid (or DNA). In eukaryotes, DNA is organised in large units called chromosomes that are located inside the cells nucleus. On these chromosomes reside functional units called genes, which encode for discrete hereditary characteristics, in most cases proteins. Multicellular organisms are composed of numerous different cell types, such as blood, skin, muscle and brain cells. This cellular diversity is extraordinary given the fact that all of these individual cell types harbour the same genetic material. The functional and morphological diversity among cells is dictated by the precise regulation of genes throughout development and different stages of cellular differentiation. Incorrect spatiotemporal activation and repression of genes can lead to cellular defects, which may eventually result in diseases such as cancer. Th!
erefore, different mechanisms of control exist that regulate the transcription of genes in time and space, and understanding this transcriptional regulation in more detail is one of the key objectives in the field of molecular biology.
Different cis-regulatory DNA elements like promoters, enhancers and insulators are involved in the regulated expression of protein coding genes throughout development. An important question is how these distal cis-regulatory DNA elements communicate over distance to activate tissue- and developmental stage-specific gene expression. In this thesis, the mouse β-globin locus is used as a model system to study transcriptional regulation in the context of the living nucleus. The genes of this locus all encode for the β-globin like protein that together with α-globin and heme forms a functional hemoglobin molecule, which is capable of binding oxygen and carbon dioxide in a reversible manner in red blood cells (erythrocytes). Besides the β-globin genes, the locus contains a number of well-characterised cis-regulatory DNA elements like enhancers, promoters a
All genetic information required for the development and functioning of an organism is stored in billions of base pairs of deoxyribonucleic acid (or DNA). In eukaryotes, DNA is organised in large units called chromosomes that are located inside the cells nucleus. On these chromosomes reside functional units called genes, which encode for discrete hereditary characteristics, in most cases proteins. Multicellular organisms are composed of numerous different cell types, such as blood, skin, muscle and brain cells. This cellular diversity is extraordinary given the fact that all of these individual cell types harbour the same genetic material. The functional and morphological diversity among cells is dictated by the precise regulation of genes throughout development and different stages of cellular differentiation. Incorrect spatiotemporal activation and repression of genes can lead to cellular defects, which may eventually result in diseases such as cancer. Th!
erefore, different mechanisms of control exist that regulate the transcription of genes in time and space, and understanding this transcriptional regulation in more detail is one of the key objectives in the field of molecular biology.
Different cis-regulatory DNA elements like promoters, enhancers and insulators are involved in the regulated expression of protein coding genes throughout development. An important question is how these distal cis-regulatory DNA elements communicate over distance to activate tissue- and developmental stage-specific gene expression. In this thesis, the mouse β-globin locus is used as a model system to study transcriptional regulation in the context of the living nucleus. The genes of this locus all encode for the β-globin like protein that together with α-globin and heme forms a functional hemoglobin molecule, which is capable of binding oxygen and carbon dioxide in a reversible manner in red blood cells (erythrocytes). Besides the β-globin genes, the locus contains a number of well-characterised cis-regulatory DNA elements like enhancers, promoters
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