小柯机器人

美国格莱斯顿研究所Deepak Srivastava、Katherine S. Pollard等研究人员合作利用转录因子蛋白质相互作用组揭示心脏病的遗传决定因素。相关论文于2022年2月18日在线发表于国际学术期刊《细胞》。

研究人员假设，先天性心脏病（CHD）的遗传决定因素可能在于转录因子的蛋白质相互作用组，这些转录因子的突变会导致CHD。研究人员在人类心脏祖细胞中定义了两个转录因子（GATA4和TBX5）的相互作用组，并将结果与近9000个来自亲属三人组的外显子进行整合，发现与CHD相关的新发错义变体在相互作用组中富集。根据残基、基因和渊源特征对交互组成员的变体进行评分，研究人员确定了可能的CHD致病基因，包括表观遗传阅读器GLYR1。

GLYR1和GATA4广泛地共同占据并共同激活心脏发育基因，所确定的GLYR1错义变体破坏了与GATA4的相互作用，损害了小鼠的体外和体内功能。这种综合的蛋白质组学和遗传学方法提供了一个框架，可用于确定心脏疾病中遗传变异体的优先次序并进行研究。

据了解，CHD存在于1%的活产婴儿中，但识别致病突变仍然是一个挑战。

附：英文原文

Title: Transcription factor protein interactomes reveal genetic determinants in heart disease

Author: Barbara Gonzalez-Teran, Maureen Pittman, Franco Felix, Reuben Thomas, Desmond Richmond-Buccola, Ruth Hüttenhain, Krishna Choudhary, Elisabetta Moroni, Mauro W. Costa, Yu Huang, Arun Padmanabhan, Michael Alexanian, Clara Youngna Lee, Bonnie E.J. Maven, Kaitlen Samse-Knapp, Sarah U. Morton, Michael McGregor, Casey A. Gifford, J.G. Seidman, Christine E. Seidman, Bruce D. Gelb, Giorgio Colombo, Bruce R. Conklin, Brian L. Black, Benoit G. Bruneau, Nevan J. Krogan, Katherine S. Pollard, Deepak Srivastava

Issue&Volume: 2022-02-18

Abstract: Congenital heart disease (CHD) is present in 1% of live births, yet identificationof causal mutations remains challenging. We hypothesized that genetic determinantsfor CHDs may lie in the protein interactomes of transcription factors whose mutationscause CHDs. Defining the interactomes of two transcription factors haplo-insufficientin CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the resultswith nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants ofinteractome members based on residue, gene, and proband features identified likelyCHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes,and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a frameworkfor prioritizing and interrogating genetic variants in heart disease.

DOI: 10.1016/j.cell.2022.01.021

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00079-4