Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits

Nat Genet. 2020 Dec;52(12):1333-1345. doi: 10.1038/s41588-020-00738-2. Epub 2020 Nov 23.


Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-β-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic / genetics
  • Erythrocytes / cytology
  • Erythrocytes / physiology*
  • Gene Expression Regulation / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Phenotype*
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci / genetics
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic / genetics


  • DNA-Binding Proteins
  • SMAD1 protein, human
  • Smad1 Protein
  • Transcription Factors