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Affinity-optimizing enhancer variants disrupt development.

Fabian Lim1,2,3, Joe J Solvason1,2,4, Genevieve E Ryan1,2

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|January 17, 2024
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Summary
This summary is machine-generated.

Suboptimal binding sites in enhancers, like the ZRS limb development gene regulator, can cause polydactyly when single-nucleotide variants (SNVs) slightly increase binding affinity, leading to altered gene expression and disease.

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Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Biology

Background:

  • Enhancers regulate gene expression timing and location, harboring most disease-associated variants.
  • The ZRS (Zone of Polarizing Activity Regulatory Sequence) is a key vertebrate enhancer controlling Shh expression in limb development.
  • Human single-nucleotide variants (SNVs) in the ZRS are linked to polydactyly, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To investigate how the ZRS encodes tissue-specific activity.
  • To elucidate the mechanisms by which ZRS SNVs cause polydactyly.
  • To understand the role of binding site affinity in enhancer function and disease pathogenesis.

Main Methods:

  • Analysis of ETS binding site affinity within the ZRS.
  • Introduction of human SNVs and synthetic variants into the ZRS to assess effects on ETS-A binding affinity.
  • Evaluation of polydactyly phenotypes in relation to altered binding affinity.
  • Examination of SNV effects on other transcription factor binding sites (ETS, IRF, HOX, AP-1) in various enhancers.

Main Results:

  • ETS sites in the ZRS exhibit low binding affinity, including a highly sensitive site, ETS-A.
  • Specific human SNVs and a synthetic variant subtly increase ETS-A binding affinity (15% to ~25%), causing polydactyly with consistent penetrance and severity.
  • Increased binding affinity correlates with more severe and penetrant polydactyly phenotypes.
  • Affinity-optimizing SNVs in various transcription factor binding sites across multiple enhancers lead to gain-of-function gene expression.

Conclusions:

  • Suboptimal binding site affinity in enhancers represents a genomic vulnerability.
  • SNVs that slightly optimize binding affinity can be pathogenic, causing diseases like polydactyly.
  • Identifying affinity-optimizing SNVs offers a mechanistic approach to pinpoint causal variants in enhanceropathies.