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Regulation and Function of POU domain transcription factors, Brn-3a and Brn-3b

Budhram-Mahadio-Head, Vishwanie; (1995) Regulation and Function of POU domain transcription factors, Brn-3a and Brn-3b. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The generation of distinct cell types during development and their maintainance in adult multicellular organisms is achieved by the selective expression of cell or tissue specific proteins. The expression of the genes encoding these proteins are controlled primarily at the transcriptional level. This regulation is largely achieved by transcription factors which bind to specific DNA elements associated with the gene promoter. Cell-specific transcription has been attributed to families of regulatory proteins which show distinct expression patterns and interactions and which may be activators or repressors that modulate transcription activity. The POU domain family of transcription factors have been shown to be important for the development and function of neuronal cells. Brn-3a, a member of the POU IV subfamily of POU domain transcription factors, was isolated from a brain cDNA library and later shown to be expressed in sensory neurons. Its high homology to the nematode, C.elegans, unc-86 gene which has been shown to be an important factor in differentiation and development of sensory neurons, suggests a conserved role for Brn-3a in sensory neuronal development and function. We have isolated the POU domain of the novel but related Brn-3b protein from the sensory neuron- derived cell line, ND7. The results presented here report on the pattern of expression of these two factors, regulation of expression in ND7 cells and their role in modulation of transcriptional activity. Brn-3a mRNA expression was found predominantly in rat brain and DRG while Brn-3b transcript were detected in these tissues but also in uterus, cervix, ovary and testis. In the ND7 cell line, there was distinct but overlapping expression of these two factors, with Bm-3b being expressed at higher levels in the proliferating ND7 cells while Brn-3a mRNA expression predominated upon differentiatiation of these cells into a sensory neuronal like cell type. The mRNA expression of both Brn-3a and Brn-3b also appeared to be regulated by combinations of growth factors and by a cyclic AMP analogue. Brn-3a may be associated with the neurite outgrowth from these cells while Brn-3b may be characteristic of proliferating cells. Brn-3a and Brn-3b also have opposite and antagonistics effects on gene expression with Brn-3a activating transcription of a heterologous promoter via an octamer-related motif while Brn-3b repressed activity. Conditions which elevated Brn-3a mRNA also increased promoter activity in ND7 cells but not in BHK cells which lack endogenous Brn-3 expression. Brn-3a was also an activator of the cellular ?-internexin gene promoter while Brn-3b repressed its activity. Furthermore, Brn-3b appeared to interact with Brn-3a and modulated its effect on promoter activity, thus suggesting a mechanism of gene regulation by the interaction of these two factors. The amino terminus of the Brn-3a protein appeared to be necessary for efficient activation of the ?-internexin promoter but not of a heterologous promoter containing the octamer-related binding site. The sequence within the ?-internexin promoter that was bound by Brn-3a and Brn-3b to regulate promoter activity was distinct from the classic octamer sites recognized by many other POU proteins. This site was found to be centered at approximately -64 bases from the transcription initiation site. Furthermore, the single stranded 'coding' sequence appeared to bind the Bm-3 proteins with higher affinity than the double stranded oligonucleotide. This therefore represent a novel DNA binding site and binding pattern by these transcription factors. Thus, these transcription factors which have overlapping expression patterns and different effects on transcriptional activity in some cells may interact to modulate gene expression in specific cell types.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Regulation and Function of POU domain transcription factors, Brn-3a and Brn-3b
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Health and environmental sciences; DNA binding
URI: https://discovery.ucl.ac.uk/id/eprint/10097783
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