Elongation and termination of transcripts by RNA pol II

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DESCRIPTION (provided by applicant): The control of gene expression at the level of transcription by RNA polymerase II is central to the life of the healthy cell and is frequently corrupted in disease. During each stage of the transcription cycle, initiation, elongation and termination, the polymerase must negotiate with a DNA template that is packaged with histones into chromatin. Access by the transcription machinery to the DNA is regulated at one level through modifications of the histones on their tails. We recently identified a new class of enzymes in yeast and mammals that modify the histone tails by removing methyl groups at Lysine 4 on histone H3 (Appendix 3). This new class of demethylase enzymes belong to a family called JARID1 with one member in yeast and four in mammals. They are almost certainly targeted to individual genes to regulate their expression but we still do not know which genes they are targeted to. In budding yeast we have found that sporulation, a major program of highly regulated changes in gene expression, is severely disrupted when the JARID1 homologue (Yjr119c) is mutated. Sporulation in yeast is an excellent model for regulated gene activity during development in higher organisms. By studying when and how the sporulation program is disrupted, we aim to uncover the mechanism by which H3K4 demethylation contributes to proper control of gene activity in a complex developmental program. During elongation, pol II faces the challenge of ploughing its way through chromatin. How elongating pol II interacts with chromatin is a major open question. We found that rapid changes in H3K4 methylation occur in yeast in response to acute inhibition of transcription elongation ("transcriptional stress") (Appendix 1) and are investigating whether this mechanism is conserved in multicellular animals. Perhaps the least well understood segment of the pol II transcription cycle is termination, the process by which pol II is informed that it has reached the end of the gene and is then released from the DNA template. We proposed a new model for how termination is triggered (Appendix 2) and will investigate how this final step in the transcription cycle is controlled by properties of RNA polymerase II and associated termination factors.