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Tropomyosin 1 genetically constrains in vitro hematopoiesis.
BMC Biology ( IF 4.4 ) Pub Date : 2020-05-14 , DOI: 10.1186/s12915-020-00783-7
Christopher Stephen Thom 1, 2, 3 , Chintan D Jobaliya 4, 5 , Kimberly Lorenz 2, 3 , Jean Ann Maguire 4, 5 , Alyssa Gagne 4, 5 , Paul Gadue 4, 5 , Deborah L French 4, 5 , Benjamin Franklin Voight 2, 3, 6
Affiliation  

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.

中文翻译:


原肌球蛋白 1 在遗传上限制体外造血。



背景技术从造血性状的人类遗传学研究中鉴定因果变异和基因对于枚举这些性状背后的基本调节机制非常重要,并且最终可以增强在体外产生血小板和/或红细胞的转化努力。为了从这些数据中识别假定的因果基因,我们使用可用的血小板和红细胞特征的全基因组关联数据集进行了计算建模。结果我们的模型确定了一组基因组特征的联合集合,这些特征在已建立的性状关联和合理的候选变异中丰富。将这些位点的变异与基因表达变化联系起来的其他研究强调了原肌球蛋白 1 (TPM1) 在我们排名最高的候选基因中。 CRISPR/Cas9 介导的人诱导多能干细胞 (iPSC) 中的 TPM1 敲除增强了造血祖细胞发育,增加了巨核细胞和红系细胞的总产量。结论我们的研究结果可能有助于解释人类遗传关联并确定增强体外造血的新遗传策略。可以采用类似的性状特异性基因优先策略来帮助简化几乎任何人类性状的功能验证实验。
更新日期:2020-05-14
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