Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Departments of Genetics and Biology, Stanford University, Stanford, CA, USA.
Nat Genet. 2023 May;55(5):841-851. doi: 10.1038/s41588-023-01366-2. Epub 2023 Apr 6.
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.
转录调控表现出广泛的稳健性，但人类遗传学表明转录因子 (TF) 剂量对其敏感。要协调这些观察结果，需要在与性状相关的范围内对 TF 剂量效应进行定量研究，而这在很大程度上尚未开展。TF 在颅面形态的正常范围和与疾病相关的变异中都发挥着核心作用；因此，我们开发了一种精确调节人类面部祖细胞中 TF 水平的方法，并将其应用于与颅面变异和疾病相关的 TF（SOX9）。大多数依赖 SOX9 的调控元件 (RE) 对 SOX9 剂量的微小减少具有缓冲作用，但直接和主要受 SOX9 调控的 RE 对 SOX9 剂量的敏感性更高；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生成和 PRS 样颅面形状变异。我们提出，这些 RE 和基因是特定表型对 TF 剂量敏感的基础，而其他基因的缓冲则导致稳健的、非线性的剂量-表型关系。
