Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Genes & Dev. 20 (11): 1470-1484

Copyright © 2006 by Cold Spring Harbor Laboratory Press.

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

Jianchi Feng, Chunming Bi, Brian S. Clark, Rina Mady, Palak Shah, and Jhumku D. Kohtz1

Program in Neurobiology and Department of Pediatrics, Children’s Memorial Hospital and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA

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.

Key Words: Noncoding RNA • homeodomain transcription factors • forebrain development • Dlx gene regulation • ultraconserved region

Received for publication January 31, 2006. Accepted for publication March 22, 2006.

1 Corresponding author.

E-MAIL j-kohtz{at}northwestern.edu; FAX (773) 755-6344.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1416106

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells.
A. A. Sigova, A. C. Mullen, B. Molinie, S. Gupta, D. A. Orlando, M. G. Guenther, A. E. Almada, C. Lin, P. A. Sharp, C. C. Giallourakis, et al. (2013)
PNAS 110, 2876-2881
   Abstract »    Full Text »    PDF »
The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells.
T. Gutschner, M. Hammerle, M. Eissmann, J. Hsu, Y. Kim, G. Hung, A. Revenko, G. Arun, M. Stentrup, M. Gross, et al. (2013)
Cancer Res. 73, 1180-1189
   Abstract »    Full Text »    PDF »
Epigenetic Regulation by Long Noncoding RNAs.
J. T. Lee (2012)
Science 338, 1435-1439
   Abstract »    Full Text »    PDF »
The novel long non-coding RNA CRG regulates Drosophila locomotor behavior.
M. Li, S. Wen, X. Guo, B. Bai, Z. Gong, X. Liu, Y. Wang, Y. Zhou, X. Chen, L. Liu, et al. (2012)
Nucleic Acids Res. 40, 11714-11727
   Abstract »    Full Text »    PDF »
An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk.
Z. Zhu, X. Gao, Y. He, H. Zhao, Q. Yu, D. Jiang, P. Zhang, X. Ma, H. Huang, D. Dong, et al. (2012)
Cancer Res. 72, 6163-6172
   Abstract »    Full Text »    PDF »
Functional characterization of tissue-specific enhancers in the DLX5/6 locus.
R. Y. Birnbaum, D. B. Everman, K. K. Murphy, F. Gurrieri, C. E. Schwartz, and N. Ahituv (2012)
Hum. Mol. Genet. 21, 4930-4938
   Abstract »    Full Text »    PDF »
Long Noncoding RNAs in Cardiac Development and Pathophysiology.
N. Schonrock, R. P. Harvey, and J. S. Mattick (2012)
Circ. Res. 111, 1349-1362
   Abstract »    Full Text »    PDF »
The Chromatin Fingerprint of Gene Enhancer Elements.
(2012)
J. Biol. Chem. 287, 30888-30896
Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs.
V. A. Moran, R. J. Perera, and A. M. Khalil (2012)
Nucleic Acids Res. 40, 6391-6400
   Abstract »    Full Text »    PDF »
Elevation of Highly Up-regulated in Liver Cancer (HULC) by Hepatitis B Virus X Protein Promotes Hepatoma Cell Proliferation via Down-regulating p18.
Y. Du, G. Kong, X. You, S. Zhang, T. Zhang, Y. Gao, L. Ye, and X. Zhang (2012)
J. Biol. Chem. 287, 26302-26311
   Abstract »    Full Text »    PDF »
Long identical multispecies elements in plant and animal genomes.
J. Reneker, E. Lyons, G. C. Conant, J. C. Pires, M. Freeling, C.-R. Shyu, and D. Korkin (2012)
PNAS 109, E1183-E1191
   Abstract »    Full Text »    PDF »
Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma.
M. Lin, C. Eng, E. T. Hawk, M. Huang, A. J. Greisinger, J. Gu, L. M. Ellis, X. Wu, and J. Lin (2012)
Carcinogenesis 33, 841-847
   Abstract »    Full Text »    PDF »
Suppression of progenitor differentiation requires the long noncoding RNA ANCR.
M. Kretz, D. E. Webster, R. J. Flockhart, C. S. Lee, A. Zehnder, V. Lopez-Pajares, K. Qu, G. X. Y. Zheng, J. Chow, G. E. Kim, et al. (2012)
Genes & Dev. 26, 338-343
   Abstract »    Full Text »    PDF »
The long noncoding RNA Vax2os1 controls the cell cycle progression of photoreceptor progenitors in the mouse retina.
N. Meola, M. Pizzo, G. Alfano, E. M. Surace, and S. Banfi (2012)
RNA 18, 111-123
   Abstract »    Full Text »    PDF »
The genomic binding sites of a noncoding RNA.
M. D. Simon, C. I. Wang, P. V. Kharchenko, J. A. West, B. A. Chapman, A. A. Alekseyenko, M. L. Borowsky, M. I. Kuroda, and R. E. Kingston (2011)
PNAS 108, 20497-20502
   Abstract »    Full Text »    PDF »
Negative Correlation between Expression Level and Evolutionary Rate of Long Intergenic Noncoding RNAs.
D. Managadze, I. B. Rogozin, D. Chernikova, S. A. Shabalina, and E. V. Koonin (2011)
Genome Biol Evol 3, 1390-1404
   Abstract »    Full Text »    PDF »
Large Intervening Non-Coding RNA HOTAIR is Associated with Hepatocellular Carcinoma Progression.
Y. Geng, S. Xie, Q. Li, J. Ma, and G. Wang (2011)
Journal of International Medical Research 39, 2119-2128
   Abstract »    PDF »
Non-coding RNAs: could they be the answer?.
F. F. Costa (2011)
Briefings in Functional Genomics 10, 316-319
   Abstract »    Full Text »    PDF »
Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex.
S. Sharma, G. M. Findlay, H. S. Bandukwala, S. Oberdoerffer, B. Baust, Z. Li, V. Schmidt, P. G. Hogan, D. B. Sacks, and A. Rao (2011)
PNAS 108, 11381-11386
   Abstract »    Full Text »    PDF »
Non-coding RNAs as regulators of gene expression and epigenetics.
M. U. Kaikkonen, M. T. Y. Lam, and C. K. Glass (2011)
Cardiovasc Res 90, 430-440
   Abstract »    Full Text »    PDF »
SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer.
M. E. Askarian-Amiri, J. Crawford, J. D. French, C. E. Smart, M. A. Smith, M. B. Clark, K. Ru, T. R. Mercer, E. R. Thompson, S. R. Lakhani, et al. (2011)
RNA 17, 878-891
   Abstract »    Full Text »    PDF »
Child Health, Developmental Plasticity, and Epigenetic Programming.
Z. Hochberg, R. Feil, M. Constancia, M. Fraga, C. Junien, J.- C. Carel, P. Boileau, Y. Le Bouc, C. L. Deal, K. Lillycrop, et al. (2011)
Endocr. Rev. 32, 159-224
   Abstract »    Full Text »    PDF »
Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing.
J. F. Sathirapongsasuti, N. Sathira, Y. Suzuki, C. Huttenhower, and S. Sugano (2011)
Nucleic Acids Res. 39, 1967-1979
   Abstract »    Full Text »    PDF »
Spatiotemporal Regulation of Multiple Overlapping Sense and Novel Natural Antisense Transcripts at the Nrgn and Camk2n1 Gene Loci during Mouse Cerebral Corticogenesis.
K.-H. Ling, C. A. Hewitt, T. Beissbarth, L. Hyde, P.-S. Cheah, G. K. Smyth, S.-S. Tan, C. N. Hahn, T. Thomas, P. Q. Thomas, et al. (2011)
Cereb Cortex 21, 683-697
   Abstract »    Full Text »    PDF »
The Long Arm of Long Noncoding RNAs: Roles as Sensors Regulating Gene Transcriptional Programs.
X. Wang, X. Song, C. K. Glass, and M. G. Rosenfeld (2011)
Cold Spring Harb Perspect Biol 3, a003756
   Abstract »    Full Text »    PDF »
Transcribed dark matter: meaning or myth?.
C. P. Ponting and T. G. Belgard (2010)
Hum. Mol. Genet. 19, R162-R168
   Abstract »    Full Text »    PDF »
An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain.
L. Poitras, M. Yu, C. Lesage-Pelletier, R. B. MacDonald, J.-P. Gagne, G. Hatch, I. Kelly, S. P. Hamilton, J. L. R. Rubenstein, G. G. Poirier, et al. (2010)
Development 137, 3089-3097
   Abstract »    Full Text »    PDF »
Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development.
M. Minoux and F. M. Rijli (2010)
Development 137, 2605-2621
   Abstract »    Full Text »    PDF »
Evidence for bacterial origin of heat shock RNA-1.
D. S. Kim, Y. Lee, and Y. Hahn (2010)
RNA 16, 274-279
   Abstract »    Full Text »    PDF »
Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells.
J. Sheik Mohamed, P. M. Gaughwin, B. Lim, P. Robson, and L. Lipovich (2010)
RNA 16, 324-337
   Abstract »    Full Text »    PDF »
Establishing legitimacy and function in the new transcriptome.
H. van Bakel and T. R. Hughes (2009)
Briefings in Functional Genomics 8, 424-436
   Abstract »    Full Text »    PDF »
Complex architecture and regulated expression of the Sox2ot locus during vertebrate development.
P. P. Amaral, C. Neyt, S. J. Wilkins, M. E. Askarian-Amiri, S. M. Sunkin, A. C. Perkins, and J. S. Mattick (2009)
RNA 15, 2013-2027
   Abstract »    Full Text »    PDF »
An Ariadne's thread to the identification and annotation of noncoding RNAs in eukaryotes.
G. Solda, I. V. Makunin, O. U. Sezerman, A. Corradin, G. Corti, and A. Guffanti (2009)
Brief Bioinform 10, 475-489
   Abstract »    Full Text »    PDF »
Pan-vertebrate conserved non-coding sequences associated with developmental regulation.
G. Elgar (2009)
Briefings in Functional Genomics 8, 256-265
   Abstract »    Full Text »    PDF »
Long noncoding RNAs: functional surprises from the RNA world.
J. E. Wilusz, H. Sunwoo, and D. L. Spector (2009)
Genes & Dev. 23, 1494-1504
   Abstract »    Full Text »    PDF »
Conserved introns reveal novel transcripts in Drosophila melanogaster.
M. Hiller, S. Findeiss, S. Lein, M. Marz, C. Nickel, D. Rose, C. Schulz, R. Backofen, S. J. Prohaska, G. Reuter, et al. (2009)
Genome Res. 19, 1289-1300
   Abstract »    Full Text »    PDF »
Dlx1 and Mash1 Transcription Factors Control MGE and CGE Patterning and Differentiation through Parallel and Overlapping Pathways.
J. E. Long, I. Cobos, G. B. Potter, and J. L. R. Rubenstein (2009)
Cereb Cortex 19, i96-i106
   Abstract »    Full Text »    PDF »
Regulation of neural macroRNAs by the transcriptional repressor REST.
R. Johnson, C. H.-L. Teh, H. Jia, R. R. Vanisri, T. Pandey, Z.-H. Lu, N. J. Buckley, L. W. Stanton, and L. Lipovich (2009)
RNA 15, 85-96
   Abstract »    Full Text »    PDF »
Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries.
C. W. K. Chiang, A. Derti, D. Schwartz, M. F. Chou, J. N. Hirschhorn, and C.-t. Wu (2008)
Genetics 180, 2277-2293
   Abstract »    Full Text »    PDF »
Noncoding RNAs in Long-Term Memory Formation.
T. R. Mercer, M. E. Dinger, J. Mariani, K. S. Kosik, M. F. Mehler, and J. S. Mattick (2008)
Neuroscientist 14, 434-445
   Abstract »    PDF »
Dlx genes pattern mammalian jaw primordium by regulating both lower jaw-specific and upper jaw-specific genetic programs.
J. Jeong, X. Li, R. J. McEvilly, M. G. Rosenfeld, T. Lufkin, and J. L. R. Rubenstein (2008)
Development 135, 2905-2916
   Abstract »    Full Text »    PDF »
Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.
M. E. Dinger, P. P. Amaral, T. R. Mercer, K. C. Pang, S. J. Bruce, B. B. Gardiner, M. E. Askarian-Amiri, K. Ru, G. Solda, C. Simons, et al. (2008)
Genome Res. 18, 1433-1445
   Abstract »    Full Text »    PDF »
Widespread Ultraconservation Divergence in Primates.
I. Ovcharenko (2008)
Mol. Biol. Evol. 25, 1668-1676
   Abstract »    Full Text »    PDF »
An ultraconserved Hox-Pbx responsive element resides in the coding sequence of Hoxa2 and is active in rhombomere 4.
X. Lampe, O. A. Samad, A. Guiguen, C. Matis, S. Remacle, J. J. Picard, F. M. Rijli, and R. Rezsohazy (2008)
Nucleic Acids Res. 36, 3214-3225
   Abstract »    Full Text »    PDF »
Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.
N. Lo Iacono, S. Mantero, A. Chiarelli, E. Garcia, A. A. Mills, M. I. Morasso, A. Costanzo, G. Levi, L. Guerrini, and G. R. Merlo (2008)
Development 135, 1377-1388
   Abstract »    Full Text »    PDF »
The Eukaryotic Genome as an RNA Machine.
P. P. Amaral, M. E. Dinger, T. R. Mercer, and J. S. Mattick (2008)
Science 319, 1787-1789
   Abstract »    Full Text »    PDF »
Large-Scale Appearance of Ultraconserved Elements in Tetrapod Genomes and Slowdown of the Molecular Clock.
S. Stephen, M. Pheasant, I. V. Makunin, and J. S. Mattick (2008)
Mol. Biol. Evol. 25, 402-408
   Abstract »    Full Text »    PDF »
Specific expression of long noncoding RNAs in the mouse brain.
T. R. Mercer, M. E. Dinger, S. M. Sunkin, M. F. Mehler, and J. S. Mattick (2008)
PNAS 105, 716-721
   Abstract »    Full Text »    PDF »
The mRNA-like noncoding RNA Gomafu constitutes a novel nuclear domain in a subset of neurons.
M. Sone, T. Hayashi, H. Tarui, K. Agata, M. Takeichi, and S. Nakagawa (2007)
J. Cell Sci. 120, 2498-2506
   Abstract »    Full Text »    PDF »
Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease.
M. F. Mehler and J. S. Mattick (2007)
Physiol Rev 87, 799-823
   Abstract »    Full Text »    PDF »
Dlx Homeobox Genes Promote Cortical Interneuron Migration from the Basal Forebrain by Direct Repression of the Semaphorin Receptor Neuropilin-2.
T. N. Le, G. Du, M. Fonseca, Q.-P. Zhou, J. T. Wigle, and D. D. Eisenstat (2007)
J. Biol. Chem. 282, 19071-19081
   Abstract »    Full Text »    PDF »
Structured RNAs in the ENCODE selected regions of the human genome.
S. Washietl, J. S. Pedersen, J. O. Korbel, C. Stocsits, A. R. Gruber, J. Hackermuller, J. Hertel, M. Lindemeyer, K. Reiche, A. Tanzer, et al. (2007)
Genome Res. 17, 852-864
   Abstract »    Full Text »    PDF »
A new paradigm for developmental biology.
J. S. Mattick (2007)
J. Exp. Biol. 210, 1526-1547
   Abstract »    Full Text »    PDF »
RNAdb 2.0--an expanded database of mammalian non-coding RNAs.
K. C. Pang, S. Stephen, M. E. Dinger, P. G. Engstrom, B. Lenhard, and J. S. Mattick (2007)
Nucleic Acids Res. 35, D178-D182
   Abstract »    Full Text »    PDF »
Eukaryotic regulatory RNAs: an answer to the 'genome complexity' conundrum.
K. V. Prasanth and D. L. Spector (2007)
Genes & Dev. 21, 11-42
   Abstract »    Full Text »    PDF »
What Is So Special About Oskar Wild?.
W. O'Gorman and A. Akoulitchev (2006)
Sci. STKE 2006, pe51
   Abstract »    Full Text »    PDF »
Gene Control by Large Noncoding RNAs.
I. Shamovsky and E. Nudler (2006)
Sci. STKE 2006, pe40
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882