Pervasive transcription constitutes a new level of eukaryotic genome regulation

Abstract

During the past few years, it has become increasingly evident that the expression of eukaryotic genomes is far more complex than had been previously noted. The idea that the transcriptome is derived exclusively from protein-coding genes and some specific non-coding RNAs--such as snRNAs, snoRNAs, tRNAs or rRNAs--has been swept away by numerous studies indicating that RNA polymerase II can be found at almost any genomic location. Pervasive transcription is widespread and, far from being a futile process, has a crucial role in controlling gene expression and genomic plasticity. Here, we review recent findings that point to cryptic transcription as a fundamental component of the regulation of eukaryotic genomes.

Figure 1

Relative orientation of non-coding RNA and mRNA transcription. PARs (CUTs and SUTs) and PROMPTs can be transcribed from the gene promoter region—from the 5′ NDR in particular—and from intergenic regions in either sense or antisense orientation. In yeast, transcription from 3′ NDRs is mostly repressed by Isw2, and intragenic cryptic promoters are generally inhibited by Spt6, Spt16 or Set2. 5′NDR, 5′ nucleosome-depleted region; CUT, cryptic unstable transcript; Isw2, imitation switch 2; ncRNA, non-coding RNA; PAR, promoter-asssociated ncRNA; PROMPT, promoter upstream transcript; Set2, SET-domain-containing 2; Spt6/16, suppressor of Ty1 6/16.

Figure 2

Possible mechanisms for the regulation of genome expression by non-coding transcription. (A) Bidirectional PARs and mRNAs might originate from different pre-initiation complexes (PICs) and compete for the same pool of transcription factors to initiate transcription. Binding of TBP or other factors might be responsible for directing the balance towards mRNA synthesis. (B) The transcriptional interference mechanism, in which transcription factors (TFs) are displaced from the mRNA promoter by the upstream cryptic transcription, is shown. The SRG1 cryptic non-coding RNA (ncRNA) interferes with the promoter of the downstream SER3 gene through this mechanism. (C) Model for start site selection. The CUT and the mRNA have the same promoter but originate from different transcription start sites and compete for the same pool of PIC factors. An example of this type of regulation occurs at the IMD2 locus. (D) Transcription-induced chromatin modifications, in which cryptic transcription modifies promoter proximal chromatin to attenuate gene expression. The GAL10–GAL1 locus is regulated through this mechanism; cryptic transcription that originates upstream from the GAL10–GAL1 promoter induces the methylation of H3K4 and/or H3K36 by the HMTs Set1 and Set2, respectively, and tethers the Rpd3S histone deacetylase complex to attenuate gene expression of the GAL locus. CUT, cryptic unstable transcript; H3, histone H3; HMT, histone methyl transferase; IMD2, inosine monophosphate dehydrogenase 2; K, lysine; PAR, promoter-associated non-coding RNA; Rpd3S, reduced potassium dependency 3 small; SER3, serine requiring 3; Set1/2, SET-domain-comtaining 1/2; SRG1, SER3 regulatory gene; TBP, TATA binding protein.

Figure 3

Models for cis- or trans-mediated RNA-dependent regulation of gene expression. (A) Regulation in cis: when Rrp6 is delocalized or absent, the antisense CUT is stabilized and recruits HDACs, which are responsible for promoter regulation and silencing. This occurs, for example, at the PHO84 locus. (B) Regulation in trans: the CUT, which is transcribed from a distant locus and stabilized, induces the recruitment of the HMT Set1, thereby inhibiting gene transcription. The RTL non-coding RNA regulates the TY1 locus in this manner. CUT, cryptic unstable transcript; HDAC, histone deacetylase complex; HMT, histone methyl transferase; PHO84, phosphate metabolism 84; Rrp6, ribosomal RNA processing 6; RTL, antisense of LTR; Set1, SET-domain-containing 1; TY1, transposon in yeast 1.

Antonin Morillon & Julia Berretta