Genome-wide screening reveals essential roles for HOX genes and imprinted genes during caudal neurogenesis of human embryonic stem cells.

IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING
Shay Kinreich, Anna Bialer-Tsypin, Ruth Viner-Breuer, Gal Keshet, Roni Suhler, Patrick Siang Lin Lim, Tamar Golan-Lev, Ofra Yanuka, Adi Turjeman, Oren Ram, Eran Meshorer, Dieter Egli, Atilgan Yilmaz, Nissim Benvenisty
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引用次数: 0

Abstract

Mapping the essential pathways for neuronal differentiation can uncover new therapeutics and models for neurodevelopmental disorders. We thus utilized a genome-wide loss-of-function library in haploid human embryonic stem cells, differentiated into caudal neuronal cells. We show that essential genes for caudal neurogenesis are enriched for secreted and membrane proteins and that a large group of neurological conditions, including neurodegenerative disorders, manifest early neuronal phenotypes. Furthermore, essential transcription factors are enriched with homeobox (HOX) genes demonstrating synergistic regulation and surprising non-redundant functions between HOXA6 and HOXB6 paralogs. Moreover, we establish the essentialome of imprinted genes during neurogenesis, demonstrating that maternally expressed genes are non-essential in pluripotent cells and their differentiated germ layers, yet several are essential for neuronal development. These include Beckwith-Wiedemann syndrome- and Angelman syndrome-related genes, for which we suggest a novel regulatory pathway. Overall, our work identifies essential pathways for caudal neuronal differentiation and stage-specific phenotypes of neurological disorders.

全基因组筛选揭示了 HOX 基因和印记基因在人类胚胎干细胞尾部神经发生过程中的重要作用。
绘制神经元分化的重要通路图可以发现神经发育障碍的新疗法和新模型。因此,我们利用单倍体人类胚胎干细胞中的全基因组功能缺失文库,将其分化为尾部神经元细胞。我们的研究表明,尾部神经发生的重要基因富含分泌蛋白和膜蛋白,包括神经退行性疾病在内的一大批神经系统疾病都表现出早期神经元表型。此外,重要转录因子与同源染色体(HOX)基因的富集显示了协同调控作用,HOXA6 和 HOXB6 同源物之间的非冗余功能令人惊讶。此外,我们还建立了神经发生过程中印记基因的基本组,证明母系表达的基因在多能细胞及其分化的生殖层中是非基本的,但有几个基因对神经元的发育是必不可少的。这些基因包括 Beckwith-Wiedemann 综合征和 Angelman 综合征相关基因,我们提出了一种新的调控途径。总之,我们的工作确定了尾部神经元分化和神经系统疾病特定阶段表型的重要途径。
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来源期刊
Stem Cell Reports
Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY
CiteScore
10.50
自引率
1.70%
发文量
200
审稿时长
28 weeks
期刊介绍: Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.
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