Proteome-Wide Profiling of Readers for DNA Modification

Area of Science:

• Epigenetics and Molecular Biology
• Genomics and Proteomics
• Transcriptional Regulation

Background:

• DNA modifications, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), are crucial for epigenetic regulation.
• Understanding how transcription factors (TFs) recognize these modified DNA bases is key to deciphering epigenetic gene regulation, but a proteome-wide view is lacking.

Purpose of the Study:

• To comprehensively profile the binding activity of human TFs to various DNA modifications.
• To investigate the dynamic changes in TF-DNA modification interactions during mouse brain development.
• To identify novel DNA modification readers and map the regulatory networks involved.

Main Methods:

• Utilized a concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) to assess TF binding to modified DNA.
• Quantified modified DNA-binding activity for 1039 human TFs (70% of the human TF proteome).
• Monitored the modified DNA-binding activity of 600 TFs throughout mouse brain development.

Main Results:

• Generated a quantitative landscape of TF-DNA modification interactions across the human proteome.
• Identified dynamic changes in TF binding to modified DNA during mouse brain development.
• Predicted novel readers of DNA modifications and described hierarchical regulatory networks, highlighting ZNF24 and ZSCAN21 as potential 5fC readers.

Conclusions:

• This study provides a valuable resource for understanding TF-DNA modification interactions in epigenetic regulation.
• The findings elucidate the roles of DNA modification readers in transcriptional control under physiological conditions.
• The identified TF-DNA modification landscape offers new avenues for research into epigenetic mechanisms.