Affinity-optimizing enhancer variants disrupt development.

ABSTRACT: Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease^1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb⁴. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly^4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest E

SUBMITTER: Lim F 

PROVIDER: S-EPMC10830414 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature