Divergent lncRNAs Regulate Gene Expression and Lineage Differentiation in Pluripotent Cells

Abstract

Divergent lncRNAs that are transcribed in the opposite direction to nearby protein-coding genes comprise a significant proportion (∼20%) of total lncRNAs in mammalian genomes. Through genome-wide analysis, we found that the distribution of this lncRNA class strongly correlates with essential developmental regulatory genes. In pluripotent cells, divergent lncRNAs regulate the transcription of nearby genes. As an example, the divergent lncRNA Evx1as promotes transcription of its neighbor gene, EVX1, and regulates mesendodermal differentiation. At a single-cell level, early broad expression of Evx1as is followed by a rapid, high-level transcription of EVX1, supporting the idea that Evx1as plays an upstream role to facilitate EVX1 transcription. Mechanistically, Evx1as RNA binds to regulatory sites on chromatin, promotes an active chromatin state, and interacts with Mediator. Based on our analyses, we propose that the biological function of thousands of uncharacterized lncRNAs of this class may be inferred from the role of their neighboring adjacent genes.

NBR2: A former junk gene emerges as a key player in tumor suppression

“…Although our current data do not support such a hypothesis, 8 another study showed that NBR2 knockdown modestly downregulated BRCA1 mRNA level. 10 Since these studies were conducted in different cell lines with different knockdown efficiencies, it is possible that NBR2 regulation of BRCA1 expression is context dependent, and it will be important to further clarify this question in future studies.…”

The functions of long noncoding RNAs in development and stem cells

“…In the case of rescue experiments following GOF or LOF approaches, the available techniques differ in their relevance for lncRNAs acting in cis, which requires the expression of the lncRNA in the proximity of its endogenous site of transcription. Here too, the use of dCas9 can assist in recruiting the lncRNA to the target site of interest, which can be sufficient for eliciting regulatory effects (Luo et al, 2016;Shechner et al, 2015).…”

New Lncs to mesendoderm specification

“…The crosstalk between Fendrr and Foxf1 represents an example of an intriguing transcriptional and functional coupling of a divergent lncRNA with its adjacent PCG, both of which are essential for development of the same embryonic tissue. Another example of a divergent lncRNA implicated in early ME specification is Evx1as, transcribed on the opposite strand of its nearby gene Even-Skipped Homeobox 1 (Evx1) (17). EVX1 is an important homeodomain TF that promotes ME specification during mouse ESC differentiation and its expression is highly correlated with its divergent lncRNA Evx1as.…”