Transcriptome-wide noise controls lineage choice in mammalian progenitor cells
Transcriptome-wide noise controls lineage choice in mammalian progenitor cells
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DOI：
10.1038/nature06965
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发表时间：
2008-05-22
期刊：
影响因子：
64.8
通讯作者：
Huang, Sui
中科院分区：
文献类型：
--
作者：
Chang, Hannah H.;Hemberg, Martin;Huang, Sui
克隆群体中细胞间的表型变异可能是‘基因表达噪声’的一种表现(1-6)，也可能反映稳定的表型变异(7)。这种“非遗传细胞个性”(7)可能源于哺乳动物细胞中蛋白质水平的缓慢波动(8)。这些波动产生了持久的细胞个性，从而使克隆种群具有异质性。然而，目前尚不清楚这种异质性是否可以解释干细胞中细胞命运决定的随机性。在这里，我们证明了在小鼠造血祖细胞的克隆群体中，干细胞标记物SCA-1(也称为Ly6a；Ref.9)重建Sca-1的亲本分布，但仅在超过一周后才这样做。这种缓慢的松弛是由高斯混合模型描述的，该模型结合了离散亚群之间由噪声驱动的转变，暗示了一种细胞类型内隐藏的多重稳定性。尽管是克隆性的，但SCA-1的异常值有明显的转录本。尽管它们独特的基因表达谱最终恢复到中值细胞的基因表达谱，显示出一种吸引子状态，但它们持续的时间足够长，使得它们在选择红系或髓系血统时有很大不同的倾向。谱系选择的偏好与谱系特异性转录因子的表达增加有关，例如GATA1的>；200倍增加(参考。10)在易红系细胞中，或a；15倍增加PU.1(Sfpi1)(参考文献11)在易髓系细胞中表达。因此，基因表达水平的克隆性异质性不是由于单个基因表达中的独立噪声，而是反映了一个缓慢波动的转录组的亚稳定状态，该转录组在单个细胞中是不同的，并可能在细胞命运决定中控制多能祖细胞的可逆、随机启动。
Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise'(1-6), or it may reflect stable phenotypic variants(7). Such 'non-genetic cell individuality'(7) can arise from the slow fluctuations of protein levels(8) in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise- driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a > 200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a > 15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.