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

Author

Listed:
  • Aki Ushiki

    (University of California San Francisco
    University of California San Francisco)

  • Yichi Zhang

    (University of California San Francisco
    University of California San Francisco
    Tsinghua University)

  • Chenling Xiong

    (University of California San Francisco
    University of California San Francisco)

  • Jingjing Zhao

    (University of California San Francisco
    University of California San Francisco)

  • Ilias Georgakopoulos-Soares

    (University of California San Francisco
    University of California San Francisco)

  • Lauren Kane

    (University of Edinburgh)

  • Kirsty Jamieson

    (University of California San Francisco)

  • Michael J. Bamshad

    (University of Washington
    University of Washington
    Brotman-Baty Institute)

  • Deborah A. Nickerson

    (University of Washington
    Brotman-Baty Institute)

  • Yin Shen

    (University of California San Francisco
    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
    University of California San Francisco)

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.

Suggested Citation

  • 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 & Eliz, 2021. "Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22470-z
    DOI: 10.1038/s41467-021-22470-z
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    Cited by:

    1. Manon Baudic & Hiroshige Murata & Fernanda M. Bosada & Uirá Souto Melo & Takanori Aizawa & Pierre Lindenbaum & Lieve E. Maarel & Amaury Guedon & Estelle Baron & Enora Fremy & Adrien Foucal & Taisuke I, 2024. "TAD boundary deletion causes PITX2-related cardiac electrical and structural defects," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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