The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator

Abstract

The identification of ultraconserved noncoding sequences in vertebrates has been associated with developmental regulators and DNA-binding proteins. One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family. In previous experiments, we showed that Sonic hedgehog treatment of forebrain neural explants results in the activation of Dlx-2 and the novel noncoding RNA (ncRNA), Evf-1. In this report, we show that the Dlx-5/6 ultraconserved region is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA Evf-2. Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner. A stable complex containing the Evf-2 ncRNA and the Dlx-2 protein forms in vivo, suggesting that the Evf-2 ncRNA activates transcriptional activity by directly influencing Dlx-2 activity. These experiments identify a novel mechanism whereby transcription is controlled by the cooperative actions of an ncRNA and a homeodomain protein. The possibility that a subset of vertebrate ultraconserved regions may function at both the DNA and RNA level to control key developmental regulators may explain why ultraconserved sequences exhibit 90% or more conservation even after 450 million years of vertebrate evolution.

New meaning in the message: Noncoding RNAs and their role in retinal development

“…2). This has been perhaps most clearly demonstrated by work on Evf-2, a ncRNA associated with the Dlx5/6 locus (Feng et al, 2006), which is itself strongly expressed in retinal progenitors (Rapicavoli and Blackshaw, unpublished data). Evf-2 can act in trans to activate transcription at the Dlx5/6 locus by interacting with Dlx2, another Dlx family member.…”

“…In a study of a child with bilateral anophthalmia, it was discovered that the Sox2 gene lies with the intron of an ncRNA, which was named Sox2 overlapping transcript (Sox2OT) (Fantes et al, 2003) just as the Dlx6 gene lies within an intron of the ncRNA Evf-2 (Feng et al, 2006). In contrast to OSTs, Sox2OT is transcribed from the same strand as Sox2 and splices around its partnered protein coding gene.…”

Identification and Characterization of a Noncoding RNA at the Mouse Pcna Locus

“…Although genetic or epigenetic differences between normal and cancer cells might cause a different susceptibility to RNAi, the results in cancerous cells (B16F10, B16BL6 and LLC) was different, still suggesting that a regulatory system mediated by ncRNA is somehow disrupted in cancer cells (Fig. 4) Although the precise mechanism by which AK007836 activates neighboring coding gene expression is still unknown, it might be an example of a class of long ncRNAs having a positive effect on gene expression (Feng et al, 2006;Lanz et al, 1999;Ørom et al, 2010;Shamovsky et al, 2006). Accumulating evidence indicate that a variety of promoter associated ncRNAs such as promoter-associated long RNAs (PALRs), promoter-associated short RNAs (PASRs), and promoter upstream transcripts (PROMTs), etc., are involved in the protein coding gene transcription (suppression or activation) through epigenetic modification in addition to transcriptional interferences (Carninci, 2010;Costa, 2010;Han et al, 2007;Morris et al, 2008;Preker et al, 2008).…”

Epigenetic setting and reprogramming for neural cell fate determination and differentiation

“…The Evf-2 ncRNA, an alternatively spliced form of Evf-1, is expressed in immature neurons. It is transcribed from the ultraconserved region located between Dlx5 and Dlx6 and functions as an enhancer for production of these transcripts [51]. It has been proposed that Evf-2 ncRNA prevents the inhibitory actions or binding of MSX, which is also known to inhibit activation of the Wnt1 enhancer and allows DLX2 to target the Dlx5/6 enhancer region.…”