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A Role for CpG methylation mediated epigenetic transcriptional silencing during olfactory neuronal development Gin, Christopher S.W.

Abstract

Epigenetic control of chromatin structure plays a critical role in regulated transcriptional silencing in eukaryotes (Li 2002). It is associated with the inaccessibility of DNA to transcription promoting factors and is critical for gene regulation during development. DNA methylation is a mechanism of epigenetic control and leads to the silencing of genes directly by blocking transcription factors from binding to promoters and indirectly by recruiting chromatin remodelling complexes leading to chromatin condensation and exclusion of transcription factors from their binding sites. We have identified Dnmt3b as a gene that is upregulated following bulbectomy induced neurogenesis in the mouse. DNMT3b is a de novo methyltransferase which can methylate previously unmethylated genomic DNA. New patterns of methylation give rise to new patterns of stable and heritable transcriptional silencing. De novo methylation and the establishment of new methylation patterns may play a role in cell lineage refinement and cellular differentiation, silencing genes that are no longer needed in a cell lineage. Here we have examined if DNA methylation may be a potential regulator of olfactory receptor neuron development. In silico analysis of OR gene clusters showed that functional OR genes are not associated with CpG motifs of characteristically high or characteristically low methylation density suggesting that dynamic control of CpGs is a potential controller of OR gene expression during ORN development. In vivo analysis showed that both DNMT3b and the other known de novo DNA methyltransferase, DNMT3a are expressed in the olfactory epithelium from E11 to adulthood and that they are differentially and sequentially expressed by ORNs at different stages of maturation during development. We have previously generated an in vitro model of ORN development to help us understand ORN developmental events. Analyses of DNMT3b expression in the OP27 olfactory receptor cell line show that DNMT3b is not recruited to DNA replication forks. DNMT3b is thus not likely to be involved in maintenance methylation and may therefore be involved in mediating changes in transcriptional competence during ORN differentiation.

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