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Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

Item Type:Article
Title:Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis
Creators Name:Kragesteen, B.K., Spielmann, M., Paliou, C., Heinrich, V., Schöpflin, R., Esposito, A., Annunziatella, C., Bianco, S., Chiariello, A.M., Jerković, I., Harabula, I., Guckelberger, P., Pechstein, M., Wittler, L., Chan, Wi.L., Franke, M., Lupiáñez, D.G., Kraft, K., Timmermann, B., Vingron, M., Visel, A., Nicodemi, M., Mundlos, S. and Andrey, G.
Abstract: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.
Keywords:CRISPR-Cas Systems, Chromatin, Chromatin Assembly and Disassembly, Developmental Gene Expression Regulation, DNA, Forelimb, Genetic Enhancer Elements, Hindlimb, Mammalian Embryo, Molecular Conformation, Morphogenesis, Nucleic Acid Conformation, Paired Box Transcription Factors, Transgenic Mice, Animals
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:1463-1473
Date:October 2018
Official Publication:https://doi.org/10.1038/s41588-018-0221-x
PubMed:View item in PubMed

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