信号转录因子结合位点的常见突变导致红细胞性状表型发生变化，这一成果由哈佛大学Leonard I. Zon团队经过不懈努力而取得。2020年11月23日出版的《自然-遗传学》杂志发表了这一最新研究成果。

在本研究中，研究人员发现许多与红细胞（RBC）性状相关的增强子变体映射到由谱系特异性主转录因子（MTF）和响应细胞外信号的信号转录因子（STF）共同结合的增强子中。大多数增强子变体位于STF而非MTF上，扰乱各种STF（BMP /TGF-β定向SMAD或WNT诱导的TCF）与DNA的结合影响了靶基因的表达。对工程化的人血细胞和表达定量性状基因座细胞的分析证实，破坏STF的结合会导致基因表达改变。该研究结果表明，驻留在转录因子结合序列上，大多数与RBC性状相关的变异都是STF的靶序列，这表明RBC性状表型的变异可能是由于细胞改变了对细胞外刺激的反应性。

据了解，全基因组关联研究确定了与人类特征和疾病相关的基因组变异。大多数与性状相关的变体位于细胞类型特异的增强子中，但对表型变异的分子机制了解较少。

附：英文原文

Title: Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits

Author: Avik Choudhuri, Eirini Trompouki, Brian J. Abraham, Leandro M. Colli, Kian Hong Kock, William Mallard, Min-Lee Yang, Divya S. Vinjamur, Alireza Ghamari, Audrey Sporrij, Karen Hoi, Barbara Hummel, Sonja Boatman, Victoria Chan, Sierra Tseng, Satish K. Nandakumar, Song Yang, Asher Lichtig, Michael Superdock, Seraj N. Grimes, Teresa V. Bowman, Yi Zhou, Shinichiro Takahashi, Roby Joehanes, Alan B. Cantor, Daniel E. Bauer, Santhi K. Ganesh, John Rinn, Paul S. Albert, Martha L. Bulyk, Stephen J. Chanock, Richard A. Young, Leonard I. Zon

Issue&Volume: 2020-11-23

Abstract: Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-β-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.

DOI: 10.1038/s41588-020-00738-2

Source: https://www.nature.com/articles/s41588-020-00738-2