Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Science. 2023 Sep 22;381(6664):eadd1250. doi: 10.1126/science.add1250.
Short tandem repeats (STRs) are enriched in eukaryotic -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 -regulatory mechanism to target TFs to genomic sites.
短串联重复序列（STRs）在真核生物的调控元件中丰富，改变基因表达，但它们如何调节转录仍然未知。我们发现 STRs 通过直接结合 TF DNA 结合结构域，将转录因子（TF）-DNA 亲和力和表观上的结合速率调节约 70 倍，其能量影响超过许多共识基序突变。STRs 最大限度地增加了靶位点附近弱偏好微状态的数量，从而增加了 TF 的密度，其影响可以通过统计力学很好地预测。证实 STRs 也会影响细胞中的 TF 结合，仅基于体内占有率进行训练的神经网络预测的影响与体外观察到的完全相同。大约 90%的 TF 优先结合不需要类似于已知基序的 STRs，为将 TF 靶向基因组位点提供了一种 - 调控机制。
