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Developmentally regulated Shh expression is robust to TAD perturbations

Iain Williamson, View ORCID ProfileLauren Kane, Paul S. Devenney, Eve Anderson, Fiona Kilanowski, Robert E. Hill, View ORCID ProfileWendy A. Bickmore, View ORCID ProfileLaura A. Lettice
doi: https://doi.org/10.1101/609941
Iain Williamson
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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Lauren Kane
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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Paul S. Devenney
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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Eve Anderson
2Transgenic Technology, CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden Glasgow G61 1BD
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Fiona Kilanowski
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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Robert E. Hill
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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Wendy A. Bickmore
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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  • For correspondence: Wendy.Bickmore@igmm.ed.ac.uk Laura.Lettice@igmm.ed.ac.uk
Laura A. Lettice
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
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  • ORCID record for Laura A. Lettice
  • For correspondence: Wendy.Bickmore@igmm.ed.ac.uk Laura.Lettice@igmm.ed.ac.uk
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Abstract

Topologically Associating Domains (TADs) have been proposed to both guide and constrain enhancer activity. Shh is located within a TAD known to contain all its enhancers. To investigate the importance of chromatin conformation and TAD integrity on developmental gene regulation, we have manipulated the Shh TAD – creating internal deletions, deleting CTCF sites including those at TAD boundaries, as well as larger deletions and inversions of TAD boundaries. Chromosome conformation capture and fluorescence in situ hybridisation assays were used the investigate changes in chromatin conformation that result from these manipulations. Our data suggest that the substantial alteration of TAD structure has no readily detectable effect on Shh expression patterns during development – except where enhancers are deleted - and results in no detectable phenotypes. Only in the case of a larger deletion of one TAD boundary could some ectopic influence of the Shh limb enhancer be detected on a gene - Mnx1 in the neighbouring TAD. Our data suggests that, contrary to expectations, the developmental regulation of Shh expression is remarkably robust to TAD perturbations.

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Posted April 15, 2019.
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Developmentally regulated Shh expression is robust to TAD perturbations
Iain Williamson, Lauren Kane, Paul S. Devenney, Eve Anderson, Fiona Kilanowski, Robert E. Hill, Wendy A. Bickmore, Laura A. Lettice
bioRxiv 609941; doi: https://doi.org/10.1101/609941
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Developmentally regulated Shh expression is robust to TAD perturbations
Iain Williamson, Lauren Kane, Paul S. Devenney, Eve Anderson, Fiona Kilanowski, Robert E. Hill, Wendy A. Bickmore, Laura A. Lettice
bioRxiv 609941; doi: https://doi.org/10.1101/609941

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