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dc.date.accessioned2021-10-27T20:30:32Z
dc.date.available2021-10-27T20:30:32Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/1721.1/136039
dc.description.abstract© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.relation.isversionof10.1038/s41588-020-00738-2
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
dc.sourcePMC
dc.titleCommon variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits
dc.typeArticle
dc.relation.journalNature Genetics
dc.eprint.versionAuthor's final manuscript
dc.type.urihttp://purl.org/eprint/type/JournalArticle
eprint.statushttp://purl.org/eprint/status/PeerReviewed
dc.date.updated2021-08-04T18:19:30Z
dspace.orderedauthorsChoudhuri, A; Trompouki, E; Abraham, BJ; Colli, LM; Kock, KH; Mallard, W; Yang, M-L; Vinjamur, DS; Ghamari, A; Sporrij, A; Hoi, K; Hummel, B; Boatman, S; Chan, V; Tseng, S; Nandakumar, SK; Yang, S; Lichtig, A; Superdock, M; Grimes, SN; Bowman, TV; Zhou, Y; Takahashi, S; Joehanes, R; Cantor, AB; Bauer, DE; Ganesh, SK; Rinn, J; Albert, PS; Bulyk, ML; Chanock, SJ; Young, RA; Zon, LI
dspace.date.submission2021-08-04T18:19:31Z
mit.journal.volume52
mit.journal.issue12
mit.licensePUBLISHER_POLICY
mit.metadata.statusAuthority Work and Publication Information Needed


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