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Human Molecular Genetics Advance Access published online on November 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi408
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 2, 2005
Revised October 26, 2005
Accepted October 26, 2005

Article

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

Elizabeth A. Grice 1, Erin S. Rochelle 1, Eric D. Green 2, Aravinda Chakravarti 1, and Andrew S. McCallion 3*

1 McKusick - Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
3 McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine BRB Room 449 733 N. Broadway Baltimore, MD 21205; Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

* To whom correspondence should be addressed.
Andrew S. McCallion, E-mail: amccalli{at}jhmi.edu


  Abstract

Evolutionary sequence conservation is now a relatively common approach for the prediction of functional DNA sequences. However, the fraction of conserved noncoding 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 noncoding 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 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 attention on the enhancer implicated in HSCR to demonstrate that this element drives reporter expression in cell populations of the excretory system and central and peripheral nervous systems, 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.


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