Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability.
Document Type
Article
Publication Date
2-17-2017
JAX Source
Nucleic Acids Res 2017 Feb 17; 45(3):1130-1143.
Volume
45
Issue
3
First Page
1130
Last Page
1143
ISSN
1362-4962
PMID
28180284
Grant
DK100692
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 Nan mouse 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 of in vitro DNA-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. Nucleic Acids Res 2017 Feb 17; 45(3):1130-1143.
Recommended Citation
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 JH,
Peters LL,
Bieker J,
Perkins A.
Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability. Nucleic Acids Res 2017 Feb 17; 45(3):1130-1143.