Combinatorial Cis-regulation in Saccharomyces Species

Area of Science:

• Genetics
• Computational Biology
• Molecular Biology

Background:

• Transcriptional control of gene expression relies on interactions between cis-regulatory elements (CREs) and gene promoters.
• Identifying these complex regulatory interactions computationally is challenging.

Purpose of the Study:

• To develop a sensitive computational method for identifying conserved CRE combinations without genome alignments.
• To validate predicted CRE interactions using experimental data and assess their role in interspecies gene regulation.

Main Methods:

• A novel computational method was developed to identify CRE combinations with conserved spacing across multiple Saccharomyces species.
• Predicted interactions were validated using existing datasets (ChIP-seq, gene expression, Gene Ontology) and new chromatin immunoprecipitation experiments.
• Comparative genomic analysis was performed on S. cerevisiae and S. bayanus.

Main Results:

• 80% of predicted CRE combinations showed evidence of combinatorial transcriptional behavior in validation datasets.
• Experimental validation confirmed the dependence of transcription factor (TF) occupancy on predicted cofactors for specific target genes.
• The method identified differences in combinatorial cis-regulation between species, explaining observed gene expression variations.

Conclusions:

• Combinatorial cis-regulation can be inferred through multi-genome analysis.
• Inferred combinatorial cis-regulation explains species-specific differences in gene expression.
• The same CRE combinations can regulate distinct biological processes in different species.