Skip Navigation


Human Molecular Genetics Advance Access originally published online on November 3, 2005
Human Molecular Genetics 2005 14(24):3837-3845; doi:10.1093/hmg/ddi408
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
14/24/3837    most recent
ddi408v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Grice, E. A.
Right arrow Articles by McCallion, A. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grice, E. A.
Right arrow Articles by McCallion, A. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer

Elizabeth A. Grice1, Erin S. Rochelle1, Eric D. Green3, Aravinda Chakravarti1 and Andrew S. McCallion1,2,*

1McKusick-Nathans Institute of Genetic Medicine, 2Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 3Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed at: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, BRB Room 449, 733 N. Broadway, Baltimore, MD 21205, USA. Tel: +1 4432875624; Fax: +1 4106148600; Email: amccalli{at}jhmi.edu

Received September 2, 2005; Accepted October 26, 2005

Evolutionary sequence conservation is now a relatively common approach for the prediction of functional DNA sequences. However, the fraction of conserved non-coding sequences with regulatory potential is still unknown. In this study, we focus on elucidating the regulatory landscape of RET, a crucial developmental gene within which we have recently identified a regulatory Hirschsprung disease (HSCR) susceptibility variant. We report a systematic examination of conserved non-coding sequences (n=45) identified in a 220 kb interval encompassing RET. We demonstrate that most of these conserved elements are capable of enhancer or suppressor activity in vitro, and the majority of the elements exert cell type-dependent control. We show that discrete sequences within regulatory elements can bind nuclear protein in a cell type-dependent manner that is consistent with their identified in vitro regulatory control. Finally, we focused our attention on the enhancer implicated in HSCR to demonstrate that this element drives reporter expression in cell populations of the excretory system and central nervous system (CNS) and peripheral nervous system (PNS), consistent with expression of the endogenous RET protein. Importantly, this sequence also modulates expression in the enteric nervous system consistent with its proposed role in HSCR.

{dagger} hg17, chr10: 42754810–43104810 (human); Mm3, chr6:118646816–119036816 (mouse); AC125509 and AC125512 (baboon); AC124166 (cat); AC138567 (chicken); RP43-171H18 (chimpanzee); AC124163 and AC124164 (cow); AC123973 (dog); AC124911 and AC125500 (fugu); AC122156 and AC124165 (pig); AC114881 (rat); AC135546 (tetraodon) and AC124155 (zebrafish)


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
L. de Pontual, N. A. Zaghloul, S. Thomas, E. E. Davis, D. M. Mcgaughey, H. Dollfus, C. Baumann, S. L. Bessling, C. Babarit, A. Pelet, et al.
Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease
PNAS, August 18, 2009; 106(33): 13921 - 13926.
[Abstract] [Full Text] [PDF]

Home page
 Brief Funct Genomic ProteomicHome page
D. J. Epstein
Cis-regulatory mutations in human disease
Brief Funct Genomic Proteomic, July 29, 2009; (2009) elp021v1.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
Y. Cheng, D. C. King, L. C. Dore, X. Zhang, Y. Zhou, Y. Zhang, C. Dorman, D. Abebe, S. A. Kumar, F. Chiaromonte, et al.
Transcriptional enhancement by GATA1-occupied DNA segments is strongly associated with evolutionary constraint on the binding site motif
Genome Res., December 1, 2008; 18(12): 1896 - 1905.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
D. M. McGaughey, R. M. Vinton, J. Huynh, A. Al-Saif, M. A. Beer, and A. S. McCallion
Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b
Genome Res., February 1, 2008; 18(2): 252 - 260.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
L de Pontual, A Pelet, D Trochet, F Jaubert, Y Espinosa-Parrilla, A Munnich, J-F Brunet, C Goridis, J Feingold, S Lyonnet, et al.
Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus
J. Med. Genet., May 1, 2006; 43(5): 419 - 423.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
S. Fisher, E. A. Grice, R. M. Vinton, S. L. Bessling, and A. S. McCallion
Conservation of RET Regulatory Function from Human to Zebrafish Without Sequence Similarity
Science, April 14, 2006; 312(5771): 276 - 279.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.