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This review focuses on the roles of cis- and trans-acting factors that …
Biology Articles » Molecular Biology » Multiple links between transcription and splicing » The roles of transcriptional activators in alternative splicing
The finding that promoter structure is important for alternative splicing predicts that factors that regulate alternative splicing could be acting through promoters and that cell-specific alternative splicing may not simply result from the differential abundance of ubiquitous SR proteins, but from a more complex process involving cell-specific promoter occupation. However, promoters are not swapped in nature, and because most genes have a single promoter, the only conceivable way by which promoter architecture could control alternative splicing in vivo should be the differential occupation of promoters by transcription factors of different natures and/or mechanistic properties. Accordingly, it has been found that transcriptional activators affect alternative splicing. Class I activators (Blau et al. 1996), such as SW6, Sp1 and CTF/NF1, which only stimulate transcriptional initiation, have little effect on EDI splicing. On the contrary, class IIB activators such as VP16, which stimulate both initiation and elongation, provoke EDI exon skipping. HIV-1 Tat, a member of class IIA activators, which has little effect on transcription in the absence of other activators, has no effect on EDI splicing. However, Tat synergizes with SW6, Sp1, and CTF, but not with VP16, in promoting transcriptional elongation and therefore in provoking EDI exclusion (Nogués et al. 2002).
Promoters and enhancers are cis-acting elements that control gene transcription via complex networks of protein–DNA and protein–protein interactions. Whereas promoters deal with putting in place the RNA polymerase, both enhancers and promoters can control transcriptional initiation and elongation. The presence of the SV40 transcriptional enhancer near a promoter stimulates pol II elongation (Yankulov et al. 1994). Consistently, deletion of the SV40 enhancer provokes a 3–10-fold reduction in exon skipping, independently of the promoter used (Kadener et al. 2002).
Transcriptional coregulators have also been implicated in the control of alternative splicing. Steroid hormones affect the processing of pre-mRNA synthesized from steroid-sensitive promoters, but not from steroid-unresponsive promoters, in a steroid-receptor-dependent and receptor-selective manner. Several coregulators of these nuclear receptors showed differential effects on alternative splicing (Auboeuf et al. 2002, 2004a). Some coregulators act by recruiting coactivators. It was recently shown that the coactivator CoAA (coactivator activator), an hnRNP-like protein that interacts with the transcriptional coregulator TRBP, which is in turn recruited to promoters through interactions with activated nuclear receptors, regulates alternative splicing in a promoter-dependent manner. CoAA similarly enhanced transcriptional activities fired by the MMTV or CMV promoters, but only affected alternative splicing of transcripts synthesized from the progesterone-activated MMTV promoter (Auboeuf et al. 2004b). It was recently shown that transcriptional activators not only modulate alternative but also constitutive splicing in a pol II CTD-dependent manner (Rosonina et al. 2003).
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