Regulation of POU transcription factor activity by OBF1 and Sox2

Lins, Katharina (2004). Regulation of POU transcription factor activity by OBF1 and Sox2. PhD thesis The Open University.



For a cell to exert a specialized function certain genes have to be expressed, others repressed. Transcription factors, regulating this expression, do not function alone, but are often part of multi-protein complexes. Regulating a single gene with more than one transcription factor is an efficient way to integrate responses to a variety of signals using a limited number of proteins. DNA binding proteins often interact with each other and with non-DNA binding proteins in a specific arrangement. The assembly of these complexes is often highly cooperative and promotes high levels of transcriptional synergy.

The center of my thesis is the family of POU transcription factors. Specifically, I elaborate the interaction within the POU protein family, with members of other transcription factor families and with cofactors. In all cases, the assembly of the correct array of polypeptides on the DNA requires specific protein-protein and protein-DNA interactions.

As an example of POU factors interacting with each other and with a cofactor I investigated the properties of a protein-DNA complex with the B-cell-specific cofactor OBF1 and the Oct1 dimer. Depending on the DNA sequence they bind to, Oct1 dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to OBF1. In Chapter 3 I show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B-cells. OBF1 alleviates DNA sequence requirements of the Oct1 dimer on PORE-related sequences in vitro. Furthermore, OBF1 enhances POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1. Based on the biochemical data, I propose a novel Oct1 dimer arrangement when OBF1 is bound.

As an example of Oct factors interacting with members of another transcription factor family I studied the interactions of Sox2 with Oct1 and Oct4, respectively. POU and Sox transcription factors exemplify partnerships established between various transcriptional regulators during early embryonic development. The combination of Oct4 and Sox2 on DNA is considered to direct the establishment of the first three lineages in the mammalian embryo.

Although functional cooperativity between key regulator proteins is pivotal for milestone decisions in mammalian development, little is known about the underlying molecular mechanisms. The data in Chapter 4 validate experimental high-resolution structure determination, followed by model building. The study shows that Oct4 and Sox2 are able to dimerize on DNA in distinct conformational arrangements. The binding site characteristics of their target genes are responsible for the correct spatial alignment of the Velcro-like interaction domains on their surface. Interestingly, these surfaces frequently have redundant functions and are instrumental in recruiting various interacting protein partners.

In Chapter 5 I investigated how Sox2 and Oct4 regulate transcription of a target gene. The first intron of Osteopontin contains a Sox-binding site and a unique PORE to which Oct4 can either bind as a monomer or a dimer. The study reveals that Sox2-specific repression depends on an upstream Sox site and an intact PORE, although neither the Sox nor the PORE sites are negative elements on their own. A mechanism is being proposed how Sox2 represses Oct4-mediated activation of Osteopontin.

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