Abstract
Factors affecting transcriptional elongation have been characterized extensively in in vitro, single cell (yeast) and cell culture systems; however, data from the context of multicellular organisms has been relatively scarce. While studies in homogeneous cell populations have been highly informative about the underlying molecular mechanisms and prevalence of polymerase pausing, they do not reveal the biological impact of perturbing this regulation in an animal. The core components regulating pausing are expressed in all animal cells and are recruited to the majority of genes, however, disrupting their function often results in discrete phenotypic effects. Mutations in genes encoding key regulators of transcriptional pausing have been recovered from several genetic screens for specific phenotypes or interactions with specific factors in mice, zebrafish and flies. Analysis of these mutations has revealed that control of transcriptional pausing is critical for a diverse range of biological pathways essential for animal development and survival.
Highlights
Cells within a mature animal differ dramatically in their size, shape, function, longevity and ability to keep dividing even though, with few exceptions, every cell contains the same set of genes
Promoter proximal pausing is not an absolute requirement for either rapid or high induction of gene expression, but appears to be a common feature at genes that are normally expressed at some basal level, but which have the capacity to be rapidly induced by changes in cellular environment
Excessive stimulation of Positive Transcription Elongation Factor b (P-TEFb) activity often leads to increased cell proliferation; mutations that increase c-Myc activity or fuse the mixed lineage leukaemia (MLL) transcription factor to super elongation complex (SEC) components have been isolated from numerous cancers
Summary
Cells within a mature animal differ dramatically in their size, shape, function, longevity and ability to keep dividing even though, with few exceptions, every cell contains the same set of genes. Upon heat shock, activating factors trigger the release of RNAP II from promoter proximal pausing, and there is rapid increase of full-length transcripts produced from Hsp genes [5, 6] Another well-studied example of elongation control is transcription of the HIV provirus [7,8,9]. The N-terminal region of Spt (NSpt: lacking the repeats phosphorylated by P-TEFb) acts in a dominant manner to disrupt development when expressed in zebrafish embryos [37] This variant impairs the repressive function of Spt in vitro and leads to de-repression of hsp in the absence of heat shock in vivo [37]. It seems likely that in the case of dosage compensation, Spt5’s role is to promote active elongation across the gene body rather than in establishing the P-TEFb checkpoint [40]
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