小柯机器人

美国斯坦福大学医学院Joanna Wysocka等研究人员合作发现，转录因子水平的精确调控确定剂量敏感性的特征。相关论文于2023年4月6日在线发表在《自然—遗传学》杂志上。

转录因子（TF）在颅面形态的正常范围和疾病相关的变异中发挥着核心作用；因此，研究人员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SOX9，一种与颅面变异和疾病相关的TF（Pierre Robin序列，PRS）。大多数依赖SOX9的调节元件（RE）对SOX9剂量的小幅下降有缓冲作用，但直接和主要由SOX9调节的RE对SOX9剂量表现出高度的敏感性；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生成和类似PRS的颅面形状变化。研究人员提出，这种RE和基因是特定表型对TF剂量的敏感性的基础，而其他基因的缓冲作用导致了剂量与表型之间强有力的非线性关系。

据介绍，转录调控表现出广泛的稳健性，但人类遗传学表明对TF剂量的敏感性。想要调和这些观察结果，需要对转录因子在性状相关范围内的剂量效应进行定量研究，而这一研究到目前为止基本上是缺乏的。

附：英文原文

Title: Precise modulation of transcription factor levels identifies features underlying dosage sensitivity

Author: Naqvi, Sahin, Kim, Seungsoo, Hoskens, Hanne, Matthews, Harold S., Spritz, Richard A., Klein, Ophir D., Hallgrmsson, Benedikt, Swigut, Tomek, Claes, Peter, Pritchard, Jonathan K., Wysocka, Joanna

Issue&Volume: 2023-04-06

Abstract: 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.

DOI: 10.1038/s41588-023-01366-2

Source: https://www.nature.com/articles/s41588-023-01366-2

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex