Short tandem repeats bind transcription factors to tune eukaryotic gene expression

Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate transcription factor (TF)–DNA affinities and apparent on-rates by about 70-fold by directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density, with impacts well predicted by statistical mechanics. Confirming that STRs also affect TF binding in cells, neural networks trained only on in vivo occupancies predicted effects identical to those observed in vitro. Approximately 90% of TFs preferentially bound STRs that need not resemble known motifs, providing a cis -regulatory mechanism to target TFs to genomic sites. Short tandem repeats (STRs) are common within regulatory elements in eukaryotic genomes. Although changes in STR lengths often correlate with altered transcription, the mechanism by which they tune gene expression has remained mysterious. Horton et al . show that many transcription factor (TF) proteins directly bind STRs and that TF-preferred STRs need not resemble known binding sites (see the Perspective by Kuhlman). This binding can be explained and predicted by simple additive models in which repeated instances of low-affinity binding sites sum to have large effects. These findings suggest that STRs provide a regulatory mechanism to tune levels of TF binding and downstream gene expression. —Di Jiang Transcription factors directly bind repetitive sequences that need not resemble known motifs.