RNA, Genome Output and Input

Abstract

RNA, the transcriptional output of genomes, not only templates protein synthesis or directly engages in catalytic functions, but can feed back to the genome and serve as regulatory input for gene expression. Transcripts affecting the RNA abundance of other genes act by mechanisms similar to and in concert with protein factors that control transcription. Through recruitment or blocking of activating and silencing complexes to specific genomic loci, RNA and protein factors can favor transcription or lower the local gene expression potential. Most regulatory proteins enter nuclei from all directions to start the search for increased affinity to specific DNA sequences or to other proteins nearby genuine gene targets. In contrast, RNAs emerge from spatial point sources within nuclei, their encoding genes. A transcriptional burst can result in the local appearance of multiple nascent RNA copies at once, in turn increasing local nucleic acid density and RNA motif abundance before diffusion into the nuclear neighborhood. The confined initial localization of regulatory RNAs causing accumulation of protein co-factors raises the intriguing possibility that target specificity of non-coding, and probably coding, RNAs is achieved through gene/RNA positioning and spatial proximity to regulated genomic regions. Here we review examples of positional cis conservation of regulatory RNAs with respect to target genes, spatial proximity of enhancer RNAs to promoters through DNA looping and RNA-mediated formation of membrane-less structures to control chromatin structure and expression. We speculate that linear and spatial proximity between regulatory RNA-encoding genes and gene targets could possibly ease the evolutionary pressure on maintaining regulatory RNA sequence conservation.

Enhancer-Promoter Communication: It’s Not Just About Contact

“…Alternatively, contact-independent E-P communication has been proposed, a model in which information present at cis -regulatory regions is transferred to promoters even at a distance, for example by diffusion of post-translationally modified TFs at enhancers ( Karr et al, 2021 ). Enhancer RNAs or condensates may similarly facilitate transcriptional activation at a distance ( Morf et al, 2020 ). Although contact-independent E-P communication requires greater experimental validation, it offers a theoretical framework compatible with recent findings.…”

Identification of sheep lncRNAs related to the immune response to vaccines and aluminium adjuvants

“…Apart from a set of highly conserved and functionally characterised lncRNAs [35], lncRNAs show low sequence conservation. Hence, some may be functionless, function by the act of transcription itself [21,36,37], like the bidirectionally transcribed class of eRNAs [38], or have short functional elements that escape common conservation analyses. Some of the highly conserved lncRNAs identified in this work have been experimentally tested in humans.…”

Enhancers are genes that express organizational RNAs

“…Enhancer transcription is considered the best molecular indicator of enhancer activity in developmental processes (Wu et al, 2014;Arner et al, 2015;Kim et al, 2015;Carullo et al, 2020;Sartorelli and Lauberth, 2020) and cancers (Chen and Liang, 2020). There has been uncertainty about whether the resulting eRNAs are byproducts of TF binding at enhancers or are integral to enhancer action (Li et al, 2016;Schoenfelder and Fraser, 2019), but the evidence is now strongly in favor of the latter, although it is also clear that the act of transcription itself modulates enhancer activity (Pande et al, 2018;Morf et al, 2020;Pande et al, 2020). While genetic analysis by enhancer deletion may not distinguish between the loss of cis-acting DNA regulatory elements and transacting elncRNAs (Gao et al, 2020;Andergassen and Rinn, 2021), more incisive strategies such as the insertion of polyA transcription termination sites, removal of elncRNA exons, siRNA-and CRISPRi/ Cas13-directed RNA knockdown have shown that elncRNAs are required for enhancer function in diverse contexts (Maass et al, 2012;Li et al, 2013;Melo et al, 2013;Lam et al, 2014;Paralkar et al, 2014;Sun et al, 2014;Xiang et al, 2014;Yin et al, 2015;Yang et al, 2016;Isoda et al, 2017;Cajigas et al, 2018;Groff et al, 2018;Fatima et al, 2019;Lewandowski et al, 2019;Allou et al, 2021;Andergassen and Rinn, 2021;Cajigas et al, 2021;Setten et al, 2021;Zibitt et al, 2021).…”