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Development of five digits is controlled by a bipartite long-range cis-regulator

Conservation within intergenic DNA often highlights regulatory elements that control gene expression from a long range. How conservation within a single element relates to regulatory information and how internal composition relates to function is unknown. Here, we examine the structural features of...

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Autores principales: Lettice, Laura A., Williamson, Iain, Devenney, Paul S., Kilanowski, Fiona, Dorin, Julia, Hill, Robert E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978833/
https://www.ncbi.nlm.nih.gov/pubmed/24715461
http://dx.doi.org/10.1242/dev.095430
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author Lettice, Laura A.
Williamson, Iain
Devenney, Paul S.
Kilanowski, Fiona
Dorin, Julia
Hill, Robert E.
author_facet Lettice, Laura A.
Williamson, Iain
Devenney, Paul S.
Kilanowski, Fiona
Dorin, Julia
Hill, Robert E.
author_sort Lettice, Laura A.
collection PubMed
description Conservation within intergenic DNA often highlights regulatory elements that control gene expression from a long range. How conservation within a single element relates to regulatory information and how internal composition relates to function is unknown. Here, we examine the structural features of the highly conserved ZRS (also called MFCS1) cis-regulator responsible for the spatiotemporal control of Shh in the limb bud. By systematically dissecting the ZRS, both in transgenic assays and within in the endogenous locus, we show that the ZRS is, in effect, composed of two distinct domains of activity: one domain directs spatiotemporal activity but functions predominantly from a short range, whereas a second domain is required to promote long-range activity. We show further that these two domains encode activities that are highly integrated and that the second domain is crucial in promoting the chromosomal conformational changes correlated with gene activity. During limb bud development, these activities encoded by the ZRS are interpreted differently by the fore limbs and the hind limbs; in the absence of the second domain there is no Shh activity in the fore limb, and in the hind limb low levels of Shh lead to a variant digit pattern ranging from two to four digits. Hence, in the embryo, the second domain stabilises the developmental programme providing a buffer for SHH morphogen activity and this ensures that five digits form in both sets of limbs.
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spelling pubmed-39788332014-05-14 Development of five digits is controlled by a bipartite long-range cis-regulator Lettice, Laura A. Williamson, Iain Devenney, Paul S. Kilanowski, Fiona Dorin, Julia Hill, Robert E. Development Research Articles Conservation within intergenic DNA often highlights regulatory elements that control gene expression from a long range. How conservation within a single element relates to regulatory information and how internal composition relates to function is unknown. Here, we examine the structural features of the highly conserved ZRS (also called MFCS1) cis-regulator responsible for the spatiotemporal control of Shh in the limb bud. By systematically dissecting the ZRS, both in transgenic assays and within in the endogenous locus, we show that the ZRS is, in effect, composed of two distinct domains of activity: one domain directs spatiotemporal activity but functions predominantly from a short range, whereas a second domain is required to promote long-range activity. We show further that these two domains encode activities that are highly integrated and that the second domain is crucial in promoting the chromosomal conformational changes correlated with gene activity. During limb bud development, these activities encoded by the ZRS are interpreted differently by the fore limbs and the hind limbs; in the absence of the second domain there is no Shh activity in the fore limb, and in the hind limb low levels of Shh lead to a variant digit pattern ranging from two to four digits. Hence, in the embryo, the second domain stabilises the developmental programme providing a buffer for SHH morphogen activity and this ensures that five digits form in both sets of limbs. The Company of Biologists 2014-04 /pmc/articles/PMC3978833/ /pubmed/24715461 http://dx.doi.org/10.1242/dev.095430 Text en © 2014. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Articles
Lettice, Laura A.
Williamson, Iain
Devenney, Paul S.
Kilanowski, Fiona
Dorin, Julia
Hill, Robert E.
Development of five digits is controlled by a bipartite long-range cis-regulator
title Development of five digits is controlled by a bipartite long-range cis-regulator
title_full Development of five digits is controlled by a bipartite long-range cis-regulator
title_fullStr Development of five digits is controlled by a bipartite long-range cis-regulator
title_full_unstemmed Development of five digits is controlled by a bipartite long-range cis-regulator
title_short Development of five digits is controlled by a bipartite long-range cis-regulator
title_sort development of five digits is controlled by a bipartite long-range cis-regulator
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978833/
https://www.ncbi.nlm.nih.gov/pubmed/24715461
http://dx.doi.org/10.1242/dev.095430
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