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体细胞干细胞中转录动力学的单分子成像

Single-molecule imaging of transcription dynamics in somatic stem cells.

作者信息

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

机构信息

Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.

Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY, USA.

出版信息

Nature. 2020 Jul;583(7816):431-436. doi: 10.1038/s41586-020-2432-4. Epub 2020 Jun 24.

DOI:10.1038/s41586-020-2432-4
PMID:32581360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8577313/
Abstract

Molecular noise is a natural phenomenon that is inherent to all biological systems. 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.

摘要

分子噪声是所有生物系统固有的一种自然现象。随机过程如何产生支持组织稳态的稳健结果仍不清楚。在这里，我们对源自造血组织的小鼠干细胞进行单分子RNA荧光原位杂交（smFISH），以测量编码转录因子的三个关键基因的转录动态：PU.1（也称为Spi1）、Gata1和Gata2。我们发现，转录的罕见随机爆发导致这些拮抗转录因子在大多数造血干细胞和祖细胞中共表达。此外，通过将smFISH与延时显微镜和谱系分析相结合，我们发现，尽管单个干细胞克隆产生的后代处于转录相关状态——类似于转录启动现象——但状态之间的潜在转变动态最好由随机和可逆模型来描述。因此，一个随机过程可以产生一些细胞行为，这些行为可能会被错误地推断为由确定性动力学产生。我们提出了一个模型，即基因表达的内在随机性促进而非阻碍转录可塑性和干细胞稳健性的同时维持。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e663/8577313/2c5e10f5b21d/nihms-1581028-f0004.jpg
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