If you have any problems related to the accessibility of any content (or if you want to request that a specific publication be accessible), please contact us at scholarworks@unr.edu.
Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability
Author
Gillinder, Kevin R.Ilsley, Melissa D.
Nebor, Danitza
Sachidanandam, Ravi
Lajoie, Mathieu
Magor, Graham W.
Tallack, Michael R.
Bailey, Timothy L.
Landsberg, Michael J.
Mackay, Joel P.
Parker, Michael W.
Miles, Luke A.
Graber, Joel H.
Peters, Luanne L.
Bieker, James J.
Perkins, Andrew C.
Date
2017Type
ArticleAbstract
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 Kruppel-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.
Permanent link
http://hdl.handle.net/11714/5436Additional Information
Journal Title | Nucleic Acids Research |
---|---|
Rights | Creative Commons Attribution-NonCommercial 4.0 International |
Rights Holder | Authors |