Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Integrative Bioinformatics, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Sci Adv. 2020 Nov 20;6(47). doi: 10.1126/sciadv.abc3851. Print 2020 Nov.
Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency. By considering equal numbers of samples from self-reported African Americans and White Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Moreover, reprogramming efficiency-associated genes are involved in diverse dynamic biological processes, including cancer and wound healing, and are predictive of 5-year breast cancer survival in an independent cohort. Candidate genes may provide insight into mechanisms of ancestry-dependent regulation of cell fate transitions and motivate additional studies for improvement of reprogramming.
诱导多能干细胞（iPSCs）可以从分化细胞中获得，通过将患者来源的 iPSCs 分化为与疾病相关的细胞系，从而生成个性化疾病模型。虽然不同 iPSC 系之间的遗传变异性会影响分化潜能，但体细胞中的这种变异性如何影响多能潜能还不太清楚。我们生成并比较了 72 对真皮成纤维细胞-iPSC 对的转录组数据，这些细胞对重编程效率有一致的变化。通过考虑来自自我报告的非裔美国人和白人美国人数目相等的样本，我们确定了与重编程效率相关的、依赖于和不依赖于祖先的转录本，这表明转录组异质性可能会显著影响重编程。此外，与重编程效率相关的基因参与了多种动态的生物学过程，包括癌症和伤口愈合，并且可以预测独立队列中 5 年乳腺癌的生存情况。候选基因可能为依赖于祖先的细胞命运转变调控机制提供深入了解，并促使进行更多的研究以改善重编程。
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