| Literature DB >> 33230299 |
Avik Choudhuri1,2, Eirini Trompouki2,3,4, Brian J Abraham5,6, Leandro M Colli7,8, Kian Hong Kock9,10, William Mallard1,11, Min-Lee Yang12, Divya S Vinjamur13, Alireza Ghamari14, Audrey Sporrij1, Karen Hoi1, Barbara Hummel3, Sonja Boatman2, Victoria Chan1, Sierra Tseng1, Satish K Nandakumar13, Song Yang2, Asher Lichtig2, Michael Superdock2, Seraj N Grimes9,15, Teresa V Bowman2,16, Yi Zhou2, Shinichiro Takahashi17, Roby Joehanes18,19, Alan B Cantor14, Daniel E Bauer13, Santhi K Ganesh12, John Rinn1,20, Paul S Albert7, Martha L Bulyk9,10,11,15,21, Stephen J Chanock7, Richard A Young5,22, Leonard I Zon23,24.
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.Entities:
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Year: 2020 PMID： 33230299 PMCID： PMC7876911 DOI： 10.1038/s41588-020-00738-2
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330