| Although eukaryotic genomes contain a wide repertoire of sequence elements, only a subset are highly transcribed during any single stage of growth. Proper regulation of various transcriptional programs enables both the cyclic behavior of dividing cells and the capacity to respond to environmental or developmental cues. Conversely, dysregulated transcription is a hallmark of many diseases including cancer.;Previous high-throughput studies have successfully employed a reductionist approach of quantitating predicted functional transcripts. Using these methods, I have characterized the cell-cycle regulated genes of the fission yeast, Schizosaccharomyces pombe, assigned putative transcription factors to many of the oscillating genes, and identified transcription programs and regulatory schemes present from yeast to man.;In subsequent studies, I have shown that far more of the genome is transcribed than is accounted for by traditional expression microarrays; unbiased measurements using high-resolution strand-specific tiling arrays revealed that processed RNAs are generated from greater than 90% of the S. pombe genome, including previously unappreciated antisense species. I have identified hundreds of discrete non-coding RNAs that result from bidirectional activity of promoters upstream of known genes, and present evidence that non-coding transcription plays an evolutionarily conserved role in genome partitioning by de-coupling co-expression of adjacent genes. Non-coding transcription also plays a direct role in regulation of gene expression. Many strong antisense transcripts are present in vegetative cells, and disproportionately represent genes exclusively expressed during mid-meiosis. I have demonstrated that antisense transcription represses expression of these genes, whose ectopic expression is often toxic to vegetative cells. Repression by antisense transcriptional interference supersedes previously proposed mechanisms for several genes, and appears to be a widespread method of regulating transcription. |
