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Published on: June 28, 2018
Nucleosomes and IDRs suppress promiscuous GCN4 binding on minichromosomes
Zelin Wei1, Oluwakemi E Abiodun1, Yick Hin Ling1,2
1Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
Nature Structural & Molecular Biology
|August 13, 2026
Summary
Transcription factors (TFs) like GCN4 efficiently find DNA targets within chromatin. Nucleosomes and TF activation domains suppress non-specific binding, ensuring accurate gene regulation.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Eukaryotic transcription factors (TFs) must locate specific DNA targets within complex chromatin.
- Previous studies focused on static TF-chromatin interactions, leaving dynamic search mechanisms unclear.
Purpose of the Study:
- To investigate how transcription activator GCN4 searches for DNA targets within chromatin compared to naked DNA.
- To elucidate the roles of nucleosome organization and TF activation domains in target search efficiency and specificity.
Main Methods:
- Utilized purified Saccharomyces cerevisiae HIS3 minichromosomes and single-molecule imaging.
- Compared association and dissociation kinetics of GCN4 on chromatin versus naked DNA.
Main Results:
- GCN4 exhibited extensive off-target binding on naked DNA due to degenerate sites and non-specific DNA interactions (1D diffusion).
- Nucleosomes reduced GCN4 residence times by hindering association and confining search to nucleosome-free regions.
- The GCN4 activation domain enhanced targeting efficiency and specificity by modulating kinetics in vitro and in vivo.
Conclusions:
- Both nucleosome organization and the GCN4 activation domain independently suppress non-specific GCN4 binding.
- This suppression prevents aberrant cryptic transcription often associated with chromatin disruptions.
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