Selective association of short tandem repeats with DNA-binding domains and intrinsically disordered regions of transcription factors.

Short tandem repeats (STRs) are enriched in regulatory regions and can bind transcription factors (TFs), as shown for selected examples in vitro. Here, we use a library-based assay to systematically measure TF binding to STRs of 2-5 bp units within budding yeast cells. We examined STR binding by four TFs, including Msn2, and further tested six Msn2 mutants, including two that contained only the DNA-binding domain (DBD) or only the 642-aa intrinsically disordered region (IDR). We find substantial STR effects on motif-dependent and motif-independent binding, which varied between TFs. For Msn2, STR association was explained by the DBD binding at motif half-sites and the IDR favoring homopurine-homopyrimidine and AT-rich repeats. TF-preferred STRs are enriched in the human genome but remain at low frequency at yeast promoters. We discuss the implications of our results for understanding the role of STRs and their crosstalk with TF IDRs in regulating TF binding across genomes.