Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia

Aki Ushiki, Yichi Zhang, Chenling Xiong, Jingjing Zhao, Ilias Georgakopoulos-Soares, Lauren Kane, Kirsty Jamieson, Michael J. Bamshad, Deborah A. Nickerson, Yin Shen, Laura A. Lettice, Elizabeth Lemos Silveira-Lucas, Florence Petit and Nadav Ahituv ()
Additional contact information
Aki Ushiki: University of California San Francisco
Yichi Zhang: University of California San Francisco
Chenling Xiong: University of California San Francisco
Jingjing Zhao: University of California San Francisco
Ilias Georgakopoulos-Soares: University of California San Francisco
Lauren Kane: University of Edinburgh
Kirsty Jamieson: University of California San Francisco
Michael J. Bamshad: University of Washington
Deborah A. Nickerson: University of Washington
Yin Shen: University of California San Francisco
Laura A. Lettice: University of Edinburgh
Elizabeth Lemos Silveira-Lucas: Consultorio Genetica Clinica
Florence Petit: University of Lille, EA7364 RADEME
Nadav Ahituv: University of California San Francisco

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions.

Date: 2021
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DOI: 10.1038/s41467-021-22470-z

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