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

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Feng, Jianchi, Bi, Chunming, Clark, Brian S., Mady, Rina, Shah, Palak, Kohtz, Jhumku D.·2006·Genes & Development

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.

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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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  1. Schmidt, J.V., Levorse, J.M., and Tilghman, S.M. 1999. En- hancer competition between H19 and Igf2 does not mediate their imprinting. Proc. Natl. Acad. Sci. 96: 9733-9738.

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Authors
Feng, J., Bi, C., Clark, B. S., Mady, R., Shah, P., & Kohtz, J. D.
Affiliations
Northwestern University (US)
Venue
Genes & Development
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
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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