Short tandem repeats bind transcription factors to tune eukaryotic gene expression
Short tandem repeats bind transcription factors to tune eukaryotic gene expression
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DOI：
10.1126/science.add1250
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发表时间：
2023-09-22
期刊：
影响因子：
56.9
通讯作者：
Fordyce，Polly M.
中科院分区：
文献类型：
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作者：
Horton，Connor A.;Alexandari，Amr M.;Fordyce，Polly M.
短串联重复序列(STR)富含真核顺式调控元件，可以改变基因表达，但它们如何调控转录仍不清楚。我们发现，STR通过直接结合转录因子(Tf)DNA结合域，调节转录因子(TF)-DNA的亲和力和表观开通率约70倍，其能量影响超过许多共识基序突变。STR最大限度地增加了目标位置附近的弱优先微态数量，从而增加了Tf密度，统计力学很好地预测了影响。证实STR也会影响细胞中的转铁蛋白结合，只对体内占有率进行训练的神经网络预测的效果与体外观察到的效果相同。大约90%的转录因子优先结合不需要与已知基序相似的STR，为将转录因子靶向基因组位点提供Acis调节机制。
Short tandem repeats (STRs) are enriched in eukaryoticcis-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 acis-regulatory mechanism to target TFs to genomic sites.