Principles of regulatory information conservation between mouse and human

Area of Science:

• Evolutionary biology
• Genomics
• Molecular biology

Background:

• Understanding the evolution of gene regulation is crucial for deciphering species divergence.
• Transcription factors (TFs) play a key role in gene regulation.

Purpose of the Study:

• To investigate the evolutionary principles of gene regulatory features since the human and mouse lineages diverged.
• To compare transcription factor occupancy and associated epigenetic signals across different cell types and species.

Main Methods:

• Generated genome-wide transcription factor occupancy profiles for 34 orthologous TFs.
• Analyzed TF binding repertoires, epigenetic signals, and co-association patterns in human-mouse erythroid progenitor, lymphoblast, and embryonic stem-cell lines.
• Compared genomic distribution, binding motifs, chromatin states, and DNA methylation preferences of TF-occupied sequences.

Main Results:

• Genomic distribution, binding motifs, chromatin states, and DNA methylation preferences of TF-occupied sequences are largely conserved.
• Binding conservation varies among TFs and genomic locations, with promoter binding being more conserved than distal element binding.
• Occupancy-conserved TF-occupied sequences are often pleiotropic and co-associate with multiple TFs.
• Single nucleotide variants in regulatory regions are enriched in occupancy-conserved TF-occupied sequences.

Conclusions:

• Gene regulatory features show both conserved and divergent evolutionary patterns since human-mouse divergence.
• Promoter regions exhibit higher conservation of TF binding compared to distal regulatory elements.
• Pleiotropic TF-occupied sequences and their enrichment for regulatory variants highlight their evolutionary significance.