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Yang, Song

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Song

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Yang, Song

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Author's Publications: search.filters.isAuthorOfPublication.0aa9050f-595b-4a02-b224-6b7164603cb9

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    Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits
    (Springer Science and Business Media LLC, 2020-11-23) 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; Bauer, Daniel; Ganesh, Santhi K.; Rinn, John; Albert, Paul S.; Bulyk, Martha; Chanock, Stephen J.; Young, Richard; Zon, Leonard
    Genome-wide association studies (GWAS) reveal genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell type-specific enhancers, but the molecular mechanism by which they cause phenotypic variation is understood in only a few instances. Here, we show that a striking proportion of 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) that modulate levels of gene expression in response to extracellular signals. We find that the majority of the enhancer variants alter STF and not MTF motifs. Consequently, they perturb DNA-binding by various signaling factors including BMP/TGF-directed SMADs, WNT-induced TCFs, Hedgehog-responsive GLIs, Notch-dependent HES and affect downstream gene expression. Analysis of activity of SNPs in human CD34+ cells and eQTL analysis from the Framingham Heart Study (FHS) verifies that human alleles with disrupted STF binding lead to altered expression of genes that are upregulated during human erythroid differentiation. Our results propose that, of the RBC trait-associated variants that reside on TF binding sequences, the majority fall on DNA sequences recognized by STFs. This suggests that, in many cases, the phenotypic variation of RBC traits could be due to disruptions in STF motifs that lead to altered responsiveness to extracellular stimuli.
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    RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells
    (Springer Science and Business Media LLC, 2020-03-30) Santoriello, Cristina; Sporrij, Audrey; Yang, Song; Flynn, Ryan; Henqriques, Telmo; Dorjsuren, Bilguujin; Custo Greig, Eugenia; McCall, Wyatt; Stanhope, Meredith; Fazio, Maurizio; Superdock, Michael; Adatto, Isaac; Abraham, Brian; Kalocsay, Marian; Jurynec, Michael; Zhou, Yi; Adelman, Karen; Calo, Elizier; Zon, Leonard
    The availability of nucleotides has a direct impact on transcription. Inhibition of dihydroorate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. Progesterone additionally bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. Ddx21-deficient zebrafish show resistance to leflunomide-induced stress. On a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.