Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability

Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability. Gillinder, K., Ilsley, M., Nébor, D., Sachidanandam, R., Lajoie, M., Magor, G., Tallack, M., Bailey, T., Landsberg, M., Mackay, J., Parker, M., Miles, L., Graber, J., Peters, L., Bieker, J., & Perkins, A. Nucleic Acids Research, 45(3):1130-1143, Oxford University Press, 2017. cited By 23

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The rules of engagement between zinc finger transcription factors and DNA have been partly defined by in vitro DNA-binding and structural studies, but less is known about how these rules apply in vivo. Here, we demonstrate how a missense mutation in the second zinc finger of Krüppel-like factor-1 (KLF1) leads to degenerate DNA-binding specificity in vivo, resulting in ectopic transcription and anemia in the Nanmouse model. We employed ChIP-seq and 4sU-RNA-seq to identify aberrant DNA-binding events genome wide and ectopic transcriptional consequences of this binding. We confirmed novel sequence specificity of the mutant recombinant zinc finger domain by performing biophysical measurements ofinvitroDNA-binding affinity. Together, these results shed new light on the mechanisms by which missense mutations in DNA-binding domains of transcription factors can lead to autosomal dominant diseases. © The Author(s) 2016.

@ARTICLE{Gillinder20171130,
author={Gillinder, K.R. and Ilsley, M.D. and Nébor, D. and Sachidanandam, R. and Lajoie, M. and Magor, G.W. and Tallack, M.R. and Bailey, T. and Landsberg, M.J. and Mackay, J.P. and Parker, M.W. and Miles, L.A. and Graber, J.H. and Peters, L.L. and Bieker, J.J. and Perkins, A.C.},
title={Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability},
journal={Nucleic Acids Research},
year={2017},
volume={45},
number={3},
pages={1130-1143},
doi={10.1093/nar/gkw1014},
note={cited By 23},
url={https://www.scopus.com/inward/record.uri?eid=2-s2.0-85025175732&doi=10.1093%2fnar%2fgkw1014&partnerID=40&md5=d5756e96f0c33c47783216a9ae8210e7},
affiliation={Cancer Genomics Group, Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, QLD  4102, Australia; Jackson Laboratory, Bar Harbor, ME  04609, United States; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY  10029, United States; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD  4072, Australia; Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV  89557, United States; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD  4072, Australia; School of Life and Environmental Sciences, University of SydneyNSW  2006, Australia; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Melbourne, VIC  3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC  3052, Australia; Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY  10029, United States; Princess Alexandra Hospital, Brisbane, QLD  4102, Australia},
abstract={The rules of engagement between zinc finger transcription factors and DNA have been partly defined by in vitro DNA-binding and structural studies, but less is known about how these rules apply in vivo. Here, we demonstrate how a missense mutation in the second zinc finger of Krüppel-like factor-1 (KLF1) leads to degenerate DNA-binding specificity in vivo, resulting in ectopic transcription and anemia in the Nanmouse model. We employed ChIP-seq and 4sU-RNA-seq to identify aberrant DNA-binding events genome wide and ectopic transcriptional consequences of this binding. We confirmed novel sequence specificity of the mutant recombinant zinc finger domain by performing biophysical measurements ofinvitroDNA-binding affinity. Together, these results shed new light on the mechanisms by which missense mutations in DNA-binding domains of transcription factors can lead to autosomal dominant diseases. © The Author(s) 2016.},
keywords={kruppel like factor;  kruppel like factor 1;  messenger RNA;  transcriptome;  unclassified drug;  zinc finger protein;  DNA;  erythroid Kruppel-like factor;  kruppel like factor;  mutant protein;  protein binding;  transcriptome;  zinc finger protein, anemia;  animal cell;  animal tissue;  Article;  binding affinity;  cell viability;  chromatin immunoprecipitation;  controlled study;  down regulation;  ectopic expression;  erythroid cell;  fetus;  fetus liver;  gene expression regulation;  gene locus;  gene ontology;  genome analysis;  in vivo study;  missense mutation;  molecular recognition;  mouse;  mutational analysis;  nonhuman;  phenotype;  priority journal;  protein DNA binding;  residue analysis;  RNA sequence;  sensitivity analysis;  sequence analysis;  upregulation;  animal;  biological model;  cell line;  cell survival;  chemistry;  erythropoiesis;  genetics;  human;  metabolism;  molecular model, Animals;  Cell Line;  Cell Survival;  DNA;  Erythroid Cells;  Erythropoiesis;  Humans;  Kruppel-Like Transcription Factors;  Mice;  Models, Genetic;  Models, Molecular;  Mutant Proteins;  Mutation, Missense;  Protein Binding;  Transcriptome;  Zinc Fingers},
correspondence_address1={Perkins, A.C.; Cancer Genomics Group, Australia; email: andrew.perkins@mater.uq.edu.au},
publisher={Oxford University Press},
issn={03051048},
coden={NARHA},
pubmed_id={28180284},
language={English},
abbrev_source_title={Nucleic Acids Res.},
document_type={Article},
source={Scopus},
}

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