DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary...

Area of Science:

• Epigenetics and Genomics
• Evolutionary Biology
• Mammalian Molecular Biology

Background:

• DNA methylation is a key epigenetic modification influencing genome function, with distinct patterns observed at transcription factor (TF) binding sites versus repressed regions.
• The mechanisms establishing genome-wide and TF binding site methylation patterns remain incompletely understood.

Purpose of the Study:

• To investigate the association between DNA methylation and TF binding evolution across mammalian species.
• To identify conserved DNA methylation patterns at TF binding regions and their functional implications.

Main Methods:

• Comparative epigenomic profiling of DNA methylation in the liver of five mammalian species (human, macaque, mouse, rat, dog).
• Integration of DNA methylation data with published occupancy profiles for five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1).
• Application of classification and clustering approaches to identify conserved methylation patterns at TF binding regions.

Main Results:

• TF binding sites exhibit low or intermediate DNA methylation levels, influenced by methylation in surrounding regions.
• Distinct, species-conserved DNA methylation patterns were identified at TF binding regions, with four TFs sharing patterns and CTCF differing.
• DNA methylation gain was observed upon the evolutionary loss of TF occupancy, suggesting coordinated evolution between methylation and TF binding.

Conclusions:

• Specific DNA methylation profiles characterize TF binding, correlating with regulatory activity, chromatin context, and evolutionary trajectories.
• Epigenomic analyses reveal a role for DNA methylation in mediating TF binding changes across species.