Understanding the regulation of coding and noncoding transcription in cell populations
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Whole transcriptome analyses have unveiled the uncomfortable truth that we know less about how transcription is regulated then we thought. In addition to its role in classic promoter-driven transcription of coding RNA, it is now clear that RNA Pol II also drives abundant expression of noncoding RNA. For the majority of this the functional significance remains unclear. Moreover, its regulation and impact are hard to predict because it often proceeds in unexpected ways from cryptic promoters, including by driving convergent antisense transcription from within 3′ UTRs. This review suggests that its time to rethink how we envisage gene expression by inclusion of the regulatory architecture of the full genetic locus, and expanding our thinking to encompass the fact that we generally study cells within heterogeneous populations.
KeywordsGene expression RNA metabolism 3′-End formation Noncoding RNA Convergent antisense transcription
A further non-technical complication to interpretation of gene expression is that we typically study cells in populations. In extreme cases these are communities of functionally diversified cells such as those in stationary phase cultures or in mature yeast colonies (Aragon et al. 2008; Cap et al. 2012; Traven et al. 2012). Even standard steady-state cultures represent an aggregate of cells in different stages of the cell and metabolic cycles. Thus, an apparent low level of certain RNA in mixed populations can correspond to very high levels in just a few cells. Nowhere is this more confusing than in the expression of noncoding RNA. It is now clear that many yeast promoters are capable of bidirectional transcription, and that directionality of such promoters is controlled (Fig. 1, Tan-Wong et al. 2012). In the case of convergent antisense transcription, simultaneous forward (marked No. 1 in Fig. 1) and reverse transcription (Nos. 2 and 3) results in polymerase collision (Prescott and Proudfoot 2002). Yet evidence that sense-antisense pairs co-exit at least transiently comes from RNAi reconstitution experiments that depend on double-stranded RNA duplexes (Alcid and Tsukiyama 2014). The open question is whether transcription from within a local genomic landscape is fixed in mutually exclusive states between cells in the population, or stochastically toggles between transcriptional states within individual cells. Experiments from the Fink lab suggest that the coding/noncoding circuitry around the FLO11 locus results in fixed, but variegated expression between cells (Bumgarner et al. 2009). During the cell cycle on the other hand, coding/noncoding circuits seem to switch between states in the same cells (Granovskaia et al. 2010). Understanding how these circuits are established and controlled will be a major challenge for the future. We suggest that the dominant regulatory information stems from the promoter of the coding transcript because its transcriptional state can rewire 3′-end dynamics associated with heterologous 3′ UTRs (Swaminathan and Beilharz 2015). However, this will require much additional research before a consensus mechanism can be reached.
- Swaminathan A, Beilharz TH (2015) Epitope-tagged yeast strains reveal promoter driven changes to 3′-end formation and convergent antisense-transcription from common 3′ UTRs. Nucleic Acids Res. http://www.ncbi.nlm.nih.gov/pubmed/26481348