Large genomic insertion at the
| Autor: | Christina, Paliou, Guillaume, Andrey |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance In this study, we reexamined an old mouse mutant named Hammer toe (Hm), which arose spontaneously almost a half century ago and exhibits a limb phenotype with webbing. We revealed that a 150-kb noncoding genomic fragment that was originally located in chromosome 14 has been inserted into a genomic region proximal to Sonic hedgehog (Shh), located in chromosome 5. This inserted fragment possesses enhancer activity to induce Shh expression in the interdigital regions in Hm, which in turn down-regulates bone morphogenetic protein signaling and eventually results in syndactyly and web formation. Since the donor fragment residing in chromosome 14 has enhancer activity to induce interdigital gene expression, the Hm mutation appears to be an archetypal case of enhancer adoption. Acquisition of new cis-regulatory elements (CREs) can cause alteration of developmental gene regulation and may introduce morphological novelty in evolution. Although structural variation in the genome generated by chromosomal rearrangement is one possible source of new CREs, only a few examples are known, except for cases of retrotransposition. In this study, we show the acquisition of novel regulatory sequences as a result of large genomic insertion in the spontaneous mouse mutation Hammer toe (Hm). Hm mice exhibit syndactyly with webbing, due to suppression of interdigital cell death in limb development. We reveal that, in the Hm genome, a 150-kb noncoding DNA fragment from chromosome 14 is inserted into the region upstream of the Sonic hedgehog (Shh) promoter in chromosome 5. Phenotyping of mouse embryos with a series of CRISPR/Cas9-aided partial deletion of the 150-kb insert clearly indicated that two different regions are necessary for the syndactyly phenotype of Hm. We found that each of the two regions contains at least one enhancer for interdigital regulation. These results show that a set of enhancers brought by the large genomic insertion elicits the interdigital Shh expression and the Hm phenotype. Transcriptome analysis indicates that ectopic expression of Shh up-regulates Chordin (Chrd) that antagonizes bone morphogenetic protein signaling in the interdigital region. Indeed, Chrd-overexpressing transgenic mice recapitulated syndactyly with webbing. Thus, the Hm mutation provides an insight into enhancer acquisition as a source of creation of novel gene regulation. |
| Databáze: | OpenAIRE |
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