Reconstructing blood stem cell regulatory network models from single-cell molecular profiles
Reconstructing blood stem cell regulatory network models from single-cell molecular profiles
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DOI：
10.1073/pnas.1610609114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Gottgens, Berthold
中科院分区：
文献类型：
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作者：
Hamey, Fiona K.;Nestorowa, Sonia;Gottgens, Berthold
成年人的血液中含有各种成熟细胞，每种细胞都有特殊的功能。单个造血干细胞（hsc）在功能上已被证明可以在生物体的一生中产生所有成熟细胞类型。造血干细胞向其他谱系的分化必须在种群水平上通过单个细胞的命运决定来平衡。转录因子在调节这些决定中起着关键作用，并在有组织的调控程序中运作，可以建模为转录调控网络。由于单个HSC命运决定的失调与致命的恶性肿瘤（如白血病）有关，因此了解这些决定是如何在细胞-细胞的基础上控制的是很重要的。在这里，我们开发并应用了一种网络推理方法，利用基于2167个造血干细胞和祖细胞中48个基因的表达谱，从单细胞快照表达数据中推断动态信息的能力。这种方法使我们能够推断出重现造血干细胞向祖细胞类型分化的转录调控网络模型，重点关注巨核红细胞祖细胞和淋巴细胞引发的多能祖细胞的轨迹。通过比较这两种模型，我们确定并随后通过实验验证了转录因子Gata2对核因子，红系2 （Nfe2）和核心结合因子，runt结构域，α亚基2，易位到，3同源物（Cbfa2t3h）的调节差异。我们的方法证实了造血的已知方面，提供了关于造血干细胞分化调节的假设，并广泛适用于其他分层生物系统，以揭示调节关系。
Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyteerythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships.