Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells
Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells
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DOI：
10.1186/s13059-017-1384-y
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发表时间：
2018-01-15
期刊：
影响因子：
12.3
通讯作者：
Watt, Fiona M.
中科院分区：
文献类型：
--
作者：
Ghahramani, Arsham;Donati, Giacomo;Watt, Fiona M.
背景：经典Wnt/β-连环蛋白信号调节哺乳动物表皮内的自我更新和谱系选择。虽然角质形成细胞的Wnt信号接收的转录反应的特点是，很少有人知道的机制，角质形成细胞在Wnt接收细胞附近的增选进行细胞fate.Results的变化：为了解决这个问题，我们进行单细胞RNA测序的小鼠角质形成细胞共培养和无β-连环蛋白激活的邻近细胞。我们确定了五种不同的细胞状态，在文化中没有暴露于β-连环蛋白刺激，并表明刺激重新分配野生型亚群比例。使用时间单细胞分析，我们重建的Wnt激活诱导的细胞命运的变化从邻近的细胞。基因表达异质性在邻近细胞中降低，这种效应对于蛋白质合成相关基因最为显著。基因表达的变化伴随着向更具增殖性的干细胞状态的转变。通过整合成像和重建的顺序基因表达的变化，在状态转换过程中，我们确定转录因子，包括Smad 4和Bcl 3，负责影响的过渡在一个接触依赖manner.Conclusions：我们的数据表明，非细胞自主Wnt/β-连环蛋白信号降低转录异质性。这进一步加深了我们对表皮Wnt信号传导如何协调再生和自我更新的理解。
Background: Canonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mammalian epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterized, little is known about the mechanism by which keratinocytes in proximity to the Wnt-receiving cell are co-opted to undergo a change in cell fate.Results: To address this, we perform single-cell RNA-sequencing on mouse keratinocytes co-cultured with and without beta-catenin-activated neighbouring cells. We identify five distinct cell states in cultures that had not been exposed to the beta-catenin stimulus and show that the stimulus redistributes wild-type subpopulation proportions. Using temporal single-cell analysis, we reconstruct the cell fate change induced by Wnt activation from neighbouring cells. Gene expression heterogeneity is reduced in neighbouring cells and this effect is most dramatic for protein synthesis-associated genes. Changes in gene expression are accompanied by a shift to a more proliferative stem cell state. By integrating imaging and reconstructed sequential gene expression changes during the state transition we identify transcription factors, including Smad4 and Bcl3, that are responsible for effecting the transition in a contact-dependent manner.Conclusions: Our data indicate that non-cell autonomous Wnt/beta-catenin signalling decreases transcriptional heterogeneity. This furthers our understanding of how epidermal Wnt signalling orchestrates regeneration and self-renewal.