Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.
DNA-Binding Proteins
/ genetics
Enhancer Elements, Genetic
/ genetics
Erythrocytes
/ cytology
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
Transcription Factors
/ genetics
Transcription, Genetic
/ genetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
15
04
2019
accepted:
14
10
2020
pubmed:
25
11
2020
medline:
26
1
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33230299
doi: 10.1038/s41588-020-00738-2
pii: 10.1038/s41588-020-00738-2
pmc: PMC7876911
mid: NIHMS1660654
doi:
Substances chimiques
DNA-Binding Proteins
0
SMAD1 protein, human
0
Smad1 Protein
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1333-1345Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM123511
Pays : United States
Organisme : NIH HHS
ID : R24 OD017870
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134812
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK049216
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139672
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL032262
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Organisme : NHGRI NIH HHS
ID : R21 HG010200
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24 DK092760
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK120535
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC25195
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA213333
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK053298
Pays : United States
Organisme : NHLBI NIH HHS
ID : DP2 HL137300
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122684
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144780
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL086694
Pays : United States
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