Control of eukaryotic gene expression: gene loops and transcriptional memory

Abstract

Gene loops are dynamic structures that juxtapose promoter–terminator regions of Pol II-transcribed genes. Although first described in yeast, gene loops have now been identified in yeast and mammalian cells. Looping requires components of the transcription preinitiation complex, the pre-mRNA 30-end processing machinery, and subunits of the nuclear pore complex. Loop formation is transcription-dependent, but neither basal nor activated transcription requires looping. Rather, looping appears to affect cellular memory of recent transcriptional activity, enabling a more rapid response to subsequent stimuli. The nuclear pore has been implicated in both memory and looping. Our working model is that loops are formed and/or maintained at the nuclear pore to facilitate hand-off of Pol II form the terminator to the promoter, thereby bypassing Pol II recruitment as the rate-limiting step in reactivation of transcription. Involvement of the nuclear pore also suggests that looping might facilitate mRNA export to the cytoplasm. The technology now exists to test these ideas.

Fig. 1

Genetic interactions among RNA Pol II transcription factors. The sua7 and sua8 (RPB1) alleles were identified as suppressors of the cyc1-5000 uATG defect. The shs1 (RPB2), ssu71 (TFG1) and ssu73 (RBP9) genes were identified as suppressor of the sua7-1 cold-sensitive growth defect. The ssu72 allele was identified in the same strain as the ssu73 allele; unlike ssu73, ssu72 acts as an enhancer, rather than as a suppressor of sua7-1 (Sun and Hampsey, 1996). The rpb1 and rpb2 genes were also identified as suppressor of the ssu72-2 heat sensitive growth defect (Reyes-Reyes and Hampsey, 2007).

Fig. 2

Chromosome Conformation Capture (3C). (A) Linear depiction of a gene with promoter on the left, terminator on the right. (B) A transient gene loop formed by juxtaposition of the promoter and the terminator. (C) Schematic depiction of 3C methods to detect gene loops. The tandem primer pair in the linear structure (panel a) becomes a convergent primer pair following the 3C protocol. According to 3C, the abundance of the ligation product, as detected by PCR, is a measurement of the frequency with which two loci interact (Dekker et al., 2002; Dekker, 2006).

Fig. 3

A model for gene looping. We propose that a gene loop forms by juxtaposition of the promoter and terminator following a pioneer round of transcription. The loop is a transient structure, maintained by physical interaction between components of the transcription initiation and termination complexes. The gene loop might promote subsequent rounds of transcription by “hand-off” of Pol II from terminator to promoter, a process facilitated by the Ssu72 CTD phosphatase (Ansari and Hampsey, 2005).