Jieyuan Liu

Using the multi-agent system ARES to analyze 1,552 TF binding datasets across 10 cell types and test competing mechanisms of TF-motif dependencies in specific cellular contexts against multi-omic data, the study found that inferred mechanisms converge on three operating routes—direct sequence recognition, protein-mediated recruitment or exclusion, and regulatory context—and that predictive motifs of target TF binding were read by their conventionally 'canonical' TFs in only one third of resolved dependencies, with motif similarity associated with shared regulatory region type but not shared transcriptional outcome, whereas reader identity was associated with both, thereby separating motif identity, reader identity, and regulatory output.

Using the multi-agent system ARES to analyze 1,552 TF binding datasets across 10 cell types and test competing mechanisms of TF-motif dependencies in specific cellular contexts against multi-omic data, the study found that inferred mechanisms converge on three operating routes—direct sequence recognition, protein-mediated recruitment or exclusion, and regulatory context—and that predictive motifs of target TF binding were read by their conventionally 'canonical' TFs in only one third of resolved dependencies, with motif similarity associated with shared regulatory region type but not shared transcriptional outcome, whereas reader identity was associated with both, thereby separating motif identity, reader identity, and regulatory output.