Local regulation of gene expression by lncRNA promoters, transcription, and splicing

By J. Engreitz, Jenna E. Haines, Elizabeth M. Perez, Glen Munson, Jenny Chen, Michael Kane, P. McDonel, M. Guttman, Eric S. Lander. Nature, 2016

1,137 citations recorded by the source corpus.

Mammalian genomes are pervasively transcribed to produce thousands of long non-coding RNAs (lncRNAs). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA–protein interactions to influence the expression of nearby genes, and it has been suggested that many other lncRNAs can also act as local regulators. Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes. However, these correlations have been challenging to dissect and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers, and the process of transcription itself may contribute to gene regulation by recruiting activating factors or remodelling nucleosomes. Here we use genetic manipulation in mouse cell lines to dissect 12 genomic loci that produce lncRNAs and find that 5 of these loci influence the expression of a neighbouring gene in cis. Notably, none of these effects requires the specific lncRNA transcripts themselves and instead involves general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Furthermore, such effects are not limited to lncRNA loci: we find that four out of six protein-coding loci also influence the expression of a neighbour. These results demonstrate that cross-talk among neighbouring genes is a prevalent phenomenon that can involve multiple mechanisms and cis-regulatory signals, including a role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and non-coding genes.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8bab17fd2ea107ac31fa2afdc9eedf1391356c5e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Cohesin loss eliminates all loop domains (2017, methodology): “We therefore characterized the effects of cohesin loss on nascent transcription by performing precision nuclear run-on sequencing (PRO-Seq) in treated and untreated HCT116 cells (Engreitz et al., 2016; Jonkers and Lis, 2015) (Fig.”
Determinants of enhancer and promoter activities of regulatory elements (2019, background): “Diao (2017), Dao (2017) and Engreitz (2016) have observed, using in vivo genome editing and in vitro MPRAs, gene promoters with high enhancer strengths.”
Activity-by-Contact model of enhancer-promoter regulation from thousands of CRISPR perturbations (2019, background): “This is because the promoters of genes are known to have the potential to act as enhancers for other genes and are frequently bound by activating TFs 26,49 .”
CRISPRi-based genome-scale identification of functional long non-coding RNA loci in human cells (2016, neutral): “That our hits were enriched for multiexonic lncRNAs is consistent with the concept that lncRNA splicing can be an aspect of lncRNA function (26) (Fig.”
Genome-wide enhancer maps link risk variants to disease genes (2021, methodology): “This complexity appears to be a fundamental feature of mammalian gene regulation: cis -eQTL studies indicate that noncoding variants often regulate multiple genes 32 , and CRISPR experiments have identified individual enhancers that regulate up to eight genes in cis 4,33 .”
The multidimensional mechanisms of long noncoding RNA function (2017, background): “Although the number of loci evaluated in the study is still very limited considering the thousands of lncRNA– mRNA gene pairs present in the genome [101], none of the lncRNA loci included in the study seemed to require the lncRNA itself for the investigated cis-regulatory function [100].”