The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator
Open accessAbstract
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.
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FOXP2 is located in 7q31, close to the DLX5/6 locus (7q21), and regulates the expression of asDLX6nc, which is directly involved in the control of Dlx5 and Dlx6 expression.
“FOXP2 is located in 7q31, close to the DLX5/6 locus (7q21), and regulates the expression of a large antisense noncoding RNA of DLX6 (asDLX6nc or Evf1/2) (Vernes, et al. 2006, 2011), which is directly involved in the control of Dlx5 and Dlx6 expression (Feng, et al. 2006).”
From <i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution (2021) · cites this paper as Feng, et al. 2006
The Results section, “Evf-2 cooperates with Dlx-2 to activate the Dlx-5/6 enhancer” (page unavailable), reports that Evf-2 increases Dlx-5/6 enhancer-reporter activity in neural cell lines in a Dlx-2-dependent manner. This supports a role in transcriptional regulation, but does not establish the cited claim that Evf-2 directly controls expression of the endogenous Dlx5 and Dlx6 genes. The FOXP2 statements are attributed to the other citations in the sentence, not to Feng et al. (LLM, conf=0.84)
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Levi, G., de Lombares, C., Giuliani, C., Iannuzzi, V., Aouci, R., Garagnani, P., Franceschi, C., Grimaud-Hervé, D., & Narboux-Nême, N. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab181 · Cited by 29 · see citing works
Functional consequences of I56ii Dlx enhancer deletion in the developing mouse forebrain
Fazel Darbandi, S., Poitras, L., Monis, S., Lindtner, S., Yu, M., Hatch, G., Rubenstein, J. L., & Ekker, M. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.10.015 · Cited by 18 · see citing works
- Authors
- Feng, J., Bi, C., Clark, B. S., Mady, R., Shah, P., & Kohtz, J. D.
- Affiliations
- Northwestern University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2006-05-16
- Volume
- 20
- Issue
- 11
- Pages
- 1470-1484
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2139347946
- Cited by
- 712
- References
- 73
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 32 · 2023: 26 · 2022: 21 · 2021: 37 · 2020: 29 · 2019: 37 · 2018: 40 · 2017: 43 · 2016: 57 · 2015: 54 · 2014: 59 · 2013: 66 · 2012: 45
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- Bunning Food Allergy Institute, Ann and Robert H. Lurie Children's Hospital of Chicago
- Harvard University
- Johns Hopkins University
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD049875, R01HD044745, HD044745)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ultraconserved elements, non-coding RNA, transcriptional coactivator, homeodomain transcription factor, Sonic hedgehog, forebrain development, enhancer activation, alternative splicing, protein-RNA complex, vertebrate evolution
- MeSH terms
- Animals, Base Sequence, Cell Line, RNA, Transcription Factors, Transcription, Genetic, Alternative Splicing, In Situ Hybridization, DNA Primers, Homeodomain Proteins, Immunoprecipitation, Mice, Rats
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