Journal Article

Evaluation of the <i>RET</i> regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer

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

in Human Molecular Genetics

Volume 14, issue 24, pages 3837-3845
Published in print December 2005 | ISSN: 0964-6906
Published online November 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi408
Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer

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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.

Journal Article.  5749 words.  Illustrated.

Subjects: Genetics and Genomics

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