Tropomyosin 1 genetically constrains in vitro hematopoiesis
Tropomyosin 1 genetically constrains in vitro hematopoiesis
复制标题
DOI：
10.1186/s12915-020-00783-7
复制
发表时间：
2020-05-14
期刊：
影响因子：
5.4
通讯作者：
Voight, Benjamin Franklin
中科院分区：
文献类型：
--
作者：
Thom, Christopher Stephen;Jobaliya, Chintan D.;Voight, Benjamin Franklin
背景从人类造血性状的遗传学研究中识别因果变异和基因对于列举这些性状的基本调控机制是重要的，并最终可能在体外增加产生血小板和/或红细胞的翻译努力。为了从这些数据中识别可能的致病基因，我们使用现有的全基因组相关数据集对血小板和红细胞特征进行了计算建模。结果我们的模型确定了一个联合的基因组特征集合，丰富了已建立的性状关联和看似合理的候选变异。另外一些研究将这些基因座的变异与基因表达的变化联系起来，强调了原肌球蛋白1(TPM1)是我们的首选候选基因之一。CRISPR/Cas9介导的人诱导多能干细胞(IPSCs)中的TPM1基因敲除促进了造血祖细胞的发育，增加了总巨核细胞和红系细胞的产量。结论我们的发现可能有助于解释人类的遗传关联，并确定一种新的基因策略来增强体外造血。一种类似的针对特定特征的基因优先排序策略可以用来帮助简化几乎任何人类特征的功能验证实验。
Background Identifying causal variants and genes from human genetic studies of hematopoietic traits is important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modeling using available genome-wide association datasets for platelet and red blood cell traits. Results Our model identified a joint collection of genomic features enriched at established trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte and erythroid cell yields. Conclusions Our findings may help explain human genetic associations and identify a novel genetic strategy to enhance in vitro hematopoiesis. A similar trait-specific gene prioritization strategy could be employed to help streamline functional validation experiments for virtually any human trait.