Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.
Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.
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DOI：
10.1093/bioinformatics/btt243
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Göttgens B
中科院分区：
文献类型：
--
作者：
Bonzanni N;Garg A;Feenstra KA;Schütte J;Kinston S;Miranda-Saavedra D;Heringa J;Xenarios I;Göttgens B
动机：转录因子与顺式调控元件的组合相互作用控制着连续细胞状态的动态进展，从而支撑着所有后生动物的发育。因此，构建顺式调控元件的网络模型有可能产生对细胞命运和分化的基本见解。造血长期以来一直作为一个模型系统来研究哺乳动物的分化，但建模的基础上，实验知情的顺式调节相互作用迄今为止已被限制对相互作用的因素。在这里，我们基于连接11个造血干/祖细胞（HSPC）调节基因的详细顺式调节功能数据生成了布尔网络模型。结果如下：尽管它表面上很简单，但该模型表现出令人惊讶的复杂行为，我们在其布尔状态空间中使用强连接组件和最短路径分析绘制了这些行为。我们的模型的这种分析预测，HSPC显示异质性表达模式，并具有许多中间状态，可以作为HSPC实现最终分化状态的“垫脚石”。重要的是，需要外部扰动或“触发”来退出干细胞状态，其中不同的触发表征成熟为各种不同的谱系。通过关注红细胞分化过程中发生的中间状态，从我们的模型中，我们预测了Gata 1对Fli 1的一种新的负调控，我们通过实验证实了这一点，从而验证了我们的模型。总之，我们证明了一个先进的哺乳动物调控网络模型的基础上，实验验证的顺式调控的相互作用，使我们能够使新的，实验可检验的假设有关的转录机制，控制哺乳动物干细胞的分化。联系方式：j.heringa@ vu.nl或ioannis.xenarios@ isb-sib.ch或bg200@cam.ac.uk补充信息：补充数据可在生物信息学在线获得。
Motivation: Combinatorial interactions of transcription factors with cis-regulatory elements control the dynamic progression through successive cellular states and thus underpin all metazoan development. The construction of network models of cis-regulatory elements, therefore, has the potential to generate fundamental insights into cellular fate and differentiation. Haematopoiesis has long served as a model system to study mammalian differentiation, yet modelling based on experimentally informed cis-regulatory interactions has so far been restricted to pairs of interacting factors. Here, we have generated a Boolean network model based on detailed cis-regulatory functional data connecting 11 haematopoietic stem/progenitor cell (HSPC) regulator genes. Results: Despite its apparent simplicity, the model exhibits surprisingly complex behaviour that we charted using strongly connected components and shortest-path analysis in its Boolean state space. This analysis of our model predicts that HSPCs display heterogeneous expression patterns and possess many intermediate states that can act as ‘stepping stones’ for the HSPC to achieve a final differentiated state. Importantly, an external perturbation or ‘trigger’ is required to exit the stem cell state, with distinct triggers characterizing maturation into the various different lineages. By focusing on intermediate states occurring during erythrocyte differentiation, from our model we predicted a novel negative regulation of Fli1 by Gata1, which we confirmed experimentally thus validating our model. In conclusion, we demonstrate that an advanced mammalian regulatory network model based on experimentally validated cis-regulatory interactions has allowed us to make novel, experimentally testable hypotheses about transcriptional mechanisms that control differentiation of mammalian stem cells. Contact: j.heringa@vu.nl or ioannis.xenarios@isb-sib.ch or bg200@cam.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
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影响因子：
5.8
作者：
Bonzanni, Nicola;Krepska, Elzbieta;Heringa, Jaap
通讯作者：
Heringa, Jaap
影响因子：
56.9
作者：
Hirata, H;Yoshiura, S;Kageyama, R
通讯作者：
Kageyama, R
DOI：
10.1093/bioinformatics/btp214
发表时间：
2009-06-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Garg A;Mohanram K;Di Cara A;De Micheli G;Xenarios I
通讯作者：
Xenarios I
影响因子：
4.8
作者：
Bockamp, EO;Fordham, JL;Green, AR
通讯作者：
Green, AR
影响因子：
5.3
作者：
Kobayashi-Osaki, M;Ohneda, O;Yamamoto, M
通讯作者：
Yamamoto, M