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Cell. 2015 Apr 23;161(3):661-673. doi: 10.1016/j.cell.2015.03.003.

Human gene-centered transcription factor networks for enhancers and disease variants.

Author information

1
Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
3
Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: marian.walhout@umassmed.edu.

Abstract

Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high-throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies.

PMID:
25910213
PMCID:
PMC4409666
DOI:
10.1016/j.cell.2015.03.003
[Indexed for MEDLINE]
Free PMC Article

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