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Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits
- Source :
- Nature Genetics, Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP, Nat Genet
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 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.
- Subjects :
- Erythrocytes
Transcription, Genetic
Quantitative Trait Loci
Genome-wide association study
Biology
Polymorphism, Single Nucleotide
Article
Smad1 Protein
03 medical and health sciences
0302 clinical medicine
Transcription (biology)
Gene expression
Genetics
Humans
Genetic Predisposition to Disease
Enhancer
Transcription factor
030304 developmental biology
0303 health sciences
EXPRESSÃO GÊNICA
Phenotype
DNA-Binding Proteins
DNA binding site
Enhancer Elements, Genetic
Gene Expression Regulation
Expression quantitative trait loci
030217 neurology & neurosurgery
Genome-Wide Association Study
Transcription Factors
Subjects
Details
- ISSN :
- 15461718 and 10614036
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....f55bc07dd03b947724044bec1c014c8e