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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
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Journal Article
Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
2023
Overview
Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the
LBX1
/
FGF8
locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the
Lbx1
/
Fgf8
locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the
Lbx1
and
Btrc
genes in the apical ectodermal ridge (AER) in an
Fgf8-
like pattern induced by AER-specific enhancers of
Fgf8
. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.
Congenital limb defects are often associated with genomic rearrangements. Here they provide insights into the molecular mechanism underlying SHFM3-associated structural variations, offering a conceptual framework for how genomic rearrangements can alter gene expression and cause disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
