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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity
Nature Genetics ( IF 30.8 ) Pub Date : 2023-04-06 , DOI: 10.1038/s41588-023-01366-2
Sahin Naqvi 1, 2, 3 , Seungsoo Kim 1, 3, 4 , Hanne Hoskens 5, 6, 7 , Harold S Matthews 5, 6 , Richard A Spritz 8 , Ophir D Klein 9, 10 , Benedikt Hallgrímsson 7 , Tomek Swigut 1 , Peter Claes 5, 6, 11, 12 , Jonathan K Pritchard 2 , Joanna Wysocka 1, 3, 4
Affiliation  

Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.



中文翻译:

转录因子水平的精确调节可识别潜在的剂量敏感性特征

转录调控表现出广泛的稳健性,但人类遗传学表明对转录因子 (TF) 剂量的敏感性。调和这些观察结果需要在性状相关范围内对 TF 剂量效应进行定量研究,而这在很大程度上是迄今为止所缺乏的。转录因子在颅面形态的正常范围和疾病相关变异中起着核心作用;因此,我们开发了一种精确调节人面部祖细胞中 TF 水平的方法,并将其应用于 SOX9,这是一种与颅面变异和疾病相关的 TF(Pierre Robin 序列 (PRS))。大多数 SOX9 依赖性调节元件 (RE) 都会缓冲 SOX9 剂量的小幅下降,但直接和主要受 SOX9 调节的 RE 对 SOX9 剂量表现出更高的敏感性;这些 RE 反应部分预测了基因表达反应。敏感的 RE 和基因优先影响功能性软骨形成和 PRS 样颅面形状变异。我们提出,此类 RE 和基因是特定表型对 TF 剂量敏感性的基础,而其他基因的缓冲会导致稳健的非线性剂量-表型关系。

更新日期:2023-04-08
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