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

Choudhuri, Avik; Trompouki, Eirini; Abraham, Brian J; Colli, Leandro M; Kock, Kian Hong; Mallard, William; Yang, Min-Lee; Vinjamur, Divya S; Ghamari, Alireza; Sporrij, Audrey; Hoi, Karen; Hummel, Barbara; Boatman, Sonja; Chan, Victoria; Tseng, Sierra; Nandakumar, Satish K; Yang, Song; Lichtig, Asher; Superdock, Michael; Grimes, Seraj N; Bowman, Teresa V; Zhou, Yi; Takahashi, Shinichiro; Joehanes, Roby; Cantor, Alan B; Bauer, Daniel E; Ganesh, Santhi K; Rinn, John; Albert, Paul S; Bulyk, Martha L; Chanock, Stephen J; Young, Richard A; Zon, Leonard I

doi:10.1038/s41588-020-00738-2

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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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Item Permalink: https://hdl.handle.net/21.11116/0000-0007-85BA-1 Version Permalink: https://hdl.handle.net/21.11116/0000-0007-AB07-1

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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: Date issued: 2020-11-23

Publication Status: Issued

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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