@article{eb185eec336740df8b222d411520b3bf,
title = "Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits",
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.",
author = "Avik Choudhuri and Eirini Trompouki and Abraham, {Brian J.} and Colli, {Leandro M.} and Kock, {Kian Hong} and William Mallard and Yang, {Min Lee} and Vinjamur, {Divya S.} and Alireza Ghamari and Audrey Sporrij and Karen Hoi and Barbara Hummel and Sonja Boatman and Victoria Chan and Sierra Tseng and Nandakumar, {Satish K.} and Song Yang and Asher Lichtig and Michael Superdock and Grimes, {Seraj N.} and Bowman, {Teresa V.} and Yi Zhou and Shinichiro Takahashi and Roby Joehanes and Cantor, {Alan B.} and Bauer, {Daniel E.} and Ganesh, {Santhi K.} and John Rinn and Albert, {Paul S.} and Bulyk, {Martha L.} and Chanock, {Stephen J.} and Young, {Richard A.} and Zon, {Leonard I.}",
note = "Funding Information: We are grateful to S. Orkin, A. Wagers and C. Santoriello for the critical reading and editing of our manuscript. We thank the HHMI high-throughput sequencing facility at the Children{\textquoteright}s Hospital Boston for generating the genome-wide raw sequencing data. We acknowledge V. G. Sankaran and S. Nandakumar for providing the luciferase plasmids containing non-coding alleles of the RBM38 gene and the enhancer mutant for the RBM38 gene in K562 cells. This work was supported by the following grants to L.I.Z.—R01 HL04880, P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, 1R24OD017870-01. Additional support came from the funding by the Max Planck Society, The Fritz Thyssen Stiftung (Az 10.17.1.026MN), a Marie Curie Career Integration Grant (631432 Bloody Signals), the Deutsche Forschungsgemeinschaft DFG under Germany{\textquoteright}s Excellence Strategy (CIBSS-EXC-2189-Project-ID-390939984) and the Deutsche Forschungsgemeinschaft, Research Training Group 322977937/GRK2344 {\textquoteleft}MeInBio –BioInMe{\textquoteright} to E.T., the Hope Funds for Cancer Research Grillo-Marxuach Family Fellowship and the American Lebanese Syrian Associated Charities to B.J.A. R.A.Y. is supported by NIH grants GM123511, CA213333 and CA155258. K.H.K. is supported by an A*STAR National Science Scholarship. M.L.B. is supported by the NIH grant R21 HG010200. S.K.G. is supported by R01HL139672, R01HL122684 and R01HL086694. D.E.B. was supported by the NHLBI (P01HL32262 and DP2HL137300). The FHS is funded by National Institutes of Health contract N01-HC-25195. The eQTL work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (D. Levy, Principal Investigator). The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = dec,
doi = "10.1038/s41588-020-00738-2",
language = "English (US)",
volume = "52",
pages = "1333--1345",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "12",
}
