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在显微镜下对活细胞进行分期，揭示了分化过程中转录爆发动力学的变化。

On-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation.

机构信息

MRC Weatherall Institute for Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.

Nucleome Therapeutics Ltd., BioEscalator, The Innovation Building, Old Road Campus, Oxford, OX3 7FZ, UK.

出版信息

Nat Commun. 2022 Nov 4;13(1):6641. doi: 10.1038/s41467-022-33977-4.

DOI:10.1038/s41467-022-33977-4
PMID:36333299
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9636426/
Abstract

Determining the mechanisms by which genes are switched on and off during development is a key aim of current biomedical research. Gene transcription has been widely observed to occur in a discontinuous fashion, with short bursts of activity interspersed with periods of inactivity. It is currently not known if or how this dynamic behaviour changes as mammalian cells differentiate. To investigate this, using an on-microscope analysis, we monitored mouse α-globin transcription in live cells throughout erythropoiesis. We find that changes in the overall levels of α-globin transcription are most closely associated with changes in the fraction of time a gene spends in the active transcriptional state. We identify differences in the patterns of transcriptional bursting throughout differentiation, with maximal transcriptional activity occurring in the mid-phase of differentiation. Early in differentiation, we observe increased fluctuation in transcriptional activity whereas at the peak of gene expression, in early erythroblasts, transcription is relatively stable. Later during differentiation as α-globin expression declines, we again observe more variability in transcription within individual cells. We propose that the observed changes in transcriptional behaviour may reflect changes in the stability of active transcriptional compartments as gene expression is regulated during differentiation.

摘要

确定基因在发育过程中开启和关闭的机制是当前生物医学研究的一个关键目标。基因转录已被广泛观察到以不连续的方式发生，活性的短暂爆发与不活跃的时期交错出现。目前尚不清楚这种动态行为是否会随着哺乳动物细胞的分化而改变。为了研究这一点，我们使用显微镜分析，在红细胞生成过程中实时监测活细胞中的小鼠α-珠蛋白转录。我们发现，α-珠蛋白转录的总体水平变化与基因处于活跃转录状态的时间比例的变化最密切相关。我们在整个分化过程中发现了转录爆发模式的差异，最大的转录活性发生在分化的中期。在分化早期，我们观察到转录活性的波动增加，而在早期红细胞中基因表达的高峰期，转录相对稳定。随着分化的进行，当α-珠蛋白表达下降时，我们再次观察到单个细胞内转录的变异性增加。我们提出，观察到的转录行为变化可能反映了基因表达在分化过程中受到调节时，活性转录隔室稳定性的变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/2e7ecd06cf1d/41467_2022_33977_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/9b353d9cd68d/41467_2022_33977_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/f15be30bd9b2/41467_2022_33977_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/879d94978ddf/41467_2022_33977_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/a20fa07ba6ab/41467_2022_33977_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/887b7a5bf2d9/41467_2022_33977_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/2e7ecd06cf1d/41467_2022_33977_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/9b353d9cd68d/41467_2022_33977_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/f15be30bd9b2/41467_2022_33977_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/879d94978ddf/41467_2022_33977_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/a20fa07ba6ab/41467_2022_33977_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/887b7a5bf2d9/41467_2022_33977_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5cd/9636426/2e7ecd06cf1d/41467_2022_33977_Fig6_HTML.jpg

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