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单分子成像揭示成体细胞干细胞的转录动力学
作者:小柯机器人 发布时间:2020/6/28 10:38:20

美国阿尔伯特·爱因斯坦医学院Ulrich Steidl团队的一项最新研究利用单分子成像揭示了成体干细胞的转录动力学。相关论文于2020年6月24日在线发表于《自然》杂志。

使用单分子RNA荧光原位杂交(smFISH)研究人员对源自小鼠造血组织的干细胞进行了探究,以测量编码转录因子的三个关键基因的转录动力学:PU.1(也称为Spi1)、Gata1和Gata2。研究发现低频、随机的突发导致大多数造血干细胞和祖细胞中这些拮抗转录因子的共表达。

此外,通过将smFISH与延时显微镜配对以及谱系联合应用分析,研究人员发现,尽管单个干细胞克隆产生的子细胞处于转录相关状态(类似于转录启动现象),但通过随机和可逆模型,研究人员发现状态之间的潜在过渡动力学却能得到最佳捕获。这样,随机过程可能会产生细胞行为,该行为可能被错误地推断为是由确定性动力学引起的。研究人员提出了一个模型,其中基因表达的内在随机性促进而不是阻碍了转录可塑性和干细胞干性的维持。

据悉,分子噪声是所有生物系统固有的自然现象。尚不清楚随机过程是如何产生和维持组织动态的平衡。

附:英文原文

Title: Single-molecule imaging of transcription dynamics in somatic stem cells

Author: Justin C. Wheat, Yehonatan Sella, Michael Willcockson, Arthur I. Skoultchi, Aviv Bergman, Robert H. Singer, Ulrich Steidl

Issue&Volume: 2020-06-24

Abstract: Molecular noise is a natural phenomenon that is inherent to all biological systems1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states—akin to a transcriptional priming phenomenon—the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness.

DOI: 10.1038/s41586-020-2432-4

Source: https://www.nature.com/articles/s41586-020-2432-4

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html