Detailed understanding of protein biochemistry has led to a "protein-centric" view of regulation of cellular physiology and to the relative neglect of possible functions for noncoding RNAs, some of which have extremely highly conserved sequences in vertebrates. Feng et al. implicate such a noncoding RNA in the control of neuronal development. Earlier work from this group identified Evf-1 as a noncoding RNA expressed in response to sonic hedgehog, a regulator of developmental patterning. The current work explores the function of Evf-2 and an alternatively spliced form of Evf-1 that was also expressed in response to sonic hedgehog. Evf-2 is encoded between two genes, Dlx-5 and Dlx-6, that encode transcription factors that function during development. This intergenic region also contains the Dlx5/6 enhancer. Reporter assays in mouse neural cell lines showed that Evf-2 increased transcriptional response of the Dlx-5/6 enhancer to another member of the Dlx family of transcription factors, Dlx2. This transcriptional regulation appeared to result from interaction of Evf-2 and Dlx-2 in a molecular complex as the tagged molecules were immunoprecipitated together from transfected cells and the endogenous molecules immunoprecipitated together from embryonic rat cells. The authors propose that this interaction represents a new mode of regulation in which transcription-regulating noncoding RNAs (trRNAs) regulate the activity of homeodomain-containing transcription factors. They also note that the results also emphasize the functional importance of noncoding RNAs and help explain why the so-called ultraconserved noncoding RNA sequences show more than 90% sequence conservation after 450 million years of evolution.
J. Feng, C. Bi, B. S. Clark, R. Mady, P. Shah, J. D. Kohtz, The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20, 1470-1484 (2006). [Abstract] [Full Text]