Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis
| Autor: | Carlo Annunziatella, Verena Heinrich, Guillaume Andrey, Robert Schöpflin, Martin Franke, Christina Paliou, Katerina Kraft, Philine Guckelberger, Michael Pechstein, Bjørt K Kragesteen, Andrea M. Chiariello, Lars Wittler, Malte Spielmann, Bernd Timmermann, Stefan Mundlos, Andrea Esposito, Axel Visel, Ivana Jerković, Darío G. Lupiáñez, Martin Vingron, Simona Bianco, Mario Nicodemi, Wing Lee Chan, Izabela Harabula |
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| Přispěvatelé: | Kragesteen, B. K., Spielmann, M., Paliou, C., Riedel, FRANK HEINRICH, Schoepflin, R., Esposito, Andrea, Annunziatella, Carlo, Bianco, Simona, Chiariello, ANDREA MARIA, Jerkovic, I., Harabula, I., Guckelberger, P., Pechstein, M., Wittler, L., Chan, W. -L., Franke, M., Lupianez, D. G., Kraft, K., Timmermann, B., Vingron, M., Visel, A., Nicodemi, Mario, Mundlos, S., Andrey, G. |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal structures Enhancer Elements Regulator Molecular Conformation Mice Transgenic Biology Medical and Health Sciences Transgenic Article 03 medical and health sciences Mice Genetic Forelimb Genetics Morphogenesis Animals Paired Box Transcription Factors Developmental computer simulations Enhancer Gene Transcription factor Regulation of gene expression Mammalian Gene Expression Regulation Developmental Promoter DNA Biological Sciences Chromatin Assembly and Disassembly Embryo Mammalian Chromatin Cell biology Hindlimb 030104 developmental biology Enhancer Elements Genetic Gene Expression Regulation Embryo Nucleic Acid Conformation Polymer physic CRISPR-Cas Systems Limb morphogenesis Developmental Biology |
| Zdroj: | Nat Genet Nature Genetics, Vol. 50, No 10 (2018) pp. 1463-1473 Nature genetics, vol 50, iss 10 |
| ISSN: | 1061-4036 |
| Popis: | The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease. |
| Databáze: | OpenAIRE |
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