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Review
. 2020 Feb;11(1):3-18.
doi: 10.1080/21541264.2019.1704128. Epub 2019 Dec 19.

Lessons from eRNAs: understanding transcriptional regulation through the lens of nascent RNAs

Joseph F Cardiello  1 , Gilson J Sanchez  1 , Mary A Allen  1 , Robin D Dowell  1   2
Affiliations
Review

Lessons from eRNAs: understanding transcriptional regulation through the lens of nascent RNAs

Joseph F Cardiello et al. Transcription. 2020 Feb.

Abstract

Nascent transcription assays, such as global run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq), have uncovered a myriad of unstable RNAs being actively produced from numerous sites genome-wide. These transcripts provide a more complete and immediate picture of the impact of regulatory events. Transcription factors recruit RNA polymerase II, effectively initiating the process of transcription; repressors inhibit polymerase recruitment. Efficiency of recruitment is dictated by sequence elements in and around the RNA polymerase loading zone. A combination of sequence elements and RNA binding proteins subsequently influence the ultimate stability of the resulting transcript. Some of these transcripts are capable of providing feedback on the process, influencing subsequent transcription. By monitoring RNA polymerase activity, nascent assays provide insights into every step of the regulated process of transcription.

Keywords: RNA polymerase II; chromatin structure; eRNAs; enhancers; gene expression; nascent RNA; non-coding RNA function; transcription factors.

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Figures

Figure 1.
Figure 1.
A typical RNA polymerase II loading and initiation region. Sequence bias at RNA polymerase loading and initiation sites peaks at the epicenter of bidirectional transcription. Top: The percentage of A (red), T(blue), G(green) and C(yellow) nucleotides for all sites of RNA polymerase II loading and initiation genome wide (adapted from [44]). Bottom: Zoom in on epicenter of RNA polymerase loading and initiation, where typically two bidirectional transcription start sites (black arrows) originate from within a nucleosome free region. Rose barrels are nucleosomes.
Figure 2.
Figure 2.
The differences between stable mRNAs and other unstable nascent transcripts. (a) Cartoon showing the relationship between H3K4 methylation status (me1 and me3) and transcription (adapted from [27]). Stable transcripts include mRNAs and lncRNAs. (b) Most TFs preferentially bind non-promoter regions. Using ENCODE K562 ChIP and RefSeq annotations, the heatmap shows the fraction of ChIP sites that overlap promoters. 194 total TFs total but only every 10th row labeled. (c) Cartoon depicting early RNA processing decision. Encountering a splice site motif is correlated with message stability whereas encountering a cleavage motif is correlated with instability.
Figure 3.
Figure 3.
Active transcription factors alter local transcription and chromatin context. (a) Activation of a TF leads to recruitment of RNA polymerase II and proximal bidirectional transcription. In four separate papers, activation of specific TFs results in concomitant increases in transcription levels of eRNAs (blue positive strand, red negative strand) associated with that TF’s binding events (gray boxes) and motifs (orange dots). Data from: TP53 [135], ANDR [139,159], ESR1 [115], NF-kB [136]; motifs from HOCOMOCO [160]. All data mapped to hg19 as described in [44]. (b) Distinct functions of transcription factors (in orange) include (1) binding to DNA, (2) recruitment of RNA polymerase II (green) and (3) altering the local chromatin landscape (rose). Recruitment of RNA polymerase II may contribute to alterations in chromatin or the TF may alter chromatin distinct from RNA polymerase II recruitment. In the case of a transcriptional repressor, the repressive transcription factor disrupts recruitment of RNA Polymerase II.
Figure 4.
Figure 4.
Plethora of mechanisms where transcription at enhancers influences regulation. Top: Instances where the resulting eRNA participates in transcriptional regulation. Enhancer RNAs display functionality through physical interactions with chromatin modulators in a sequence-dependent or independent manner. Most often the presence of eRNAs results in a bias toward gene upregulation. Studies have established direct eRNA effects on transcription regulation by interacting with proteins such as: transcription factors, chromatin writers/readers, 3D chromatin structural proteins, and pausing factors [153–155,157,158]. Bottom: Instances where the act of enhancer transcription impacts transcriptional regulation. Indirect ways in which enhancer transcription itself contributes to transcription regulation include: altering transcription factors, polymerase, or general transcription factor localization, participating in transcriptional interference, or affecting chromatin rearrangements (reviewed in [29,41]).
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