TY - JOUR
T1 - Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia
AU - University of Washington Center for Mendelian Genomics
AU - Ushiki, Aki
AU - Zhang, Yichi
AU - Xiong, Chenling
AU - Zhao, Jingjing
AU - Georgakopoulos-Soares, Ilias
AU - Kane, Lauren
AU - Jamieson, Kirsty
AU - Bamshad, Michael J.
AU - Nickerson, Deborah A.
AU - Shen, Yin
AU - Lettice, Laura A.
AU - Silveira-Lucas, Elizabeth Lemos
AU - Petit, Florence
AU - Ahituv, Nadav
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104410223&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22470-z
DO - 10.1038/s41467-021-22470-z
M3 - Article
C2 - 33863876
AN - SCOPUS:85104410223
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2282
ER -