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

Choudhuri, A., Trompouki, E., Abraham, B. J., Colli, L. M., Kock, K. H., Mallard, W., et al. (2020). Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits. Nature Genetics, 52, 1333-1345. doi:10.1038/s41588-020-00738-2.

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2020
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 Creators:
Choudhuri, Avik1, Author
Trompouki, Eirini2, Author           
Abraham, Brian J1, Author
Colli, Leandro M1, Author
Kock, Kian Hong1, Author
Mallard, William1, Author
Yang, Min-Lee1, Author
Vinjamur, Divya S1, Author
Ghamari, Alireza1, Author
Sporrij, Audrey1, Author
Hoi, Karen1, Author
Hummel, Barbara3, Author
Boatman, Sonja1, Author
Chan, Victoria1, Author
Tseng, Sierra1, Author
Nandakumar, Satish K1, Author
Yang, Song1, Author
Lichtig, Asher1, Author
Superdock, Michael1, Author
Grimes, Seraj N1, Author
Bowman, Teresa V1, AuthorZhou, Yi1, AuthorTakahashi, Shinichiro1, AuthorJoehanes, Roby1, AuthorCantor, Alan B1, AuthorBauer, Daniel E1, AuthorGanesh, Santhi K1, AuthorRinn, John1, AuthorAlbert, Paul S1, AuthorBulyk, Martha L1, AuthorChanock, Stephen J1, AuthorYoung, Richard A1, AuthorZon, Leonard I1, Author more..
Affiliations:
1External Organizations, ou_persistent22              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              
3Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2020-11-23
 Publication Status: Published in print
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41588-020-00738-2
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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 52 Sequence Number: - Start / End Page: 1333 - 1345 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609