• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文会议>International Conference on Intelligent Systems for Molecular Biology >Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model
【24h】

Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model

机译：使用动态监管网络模型揭示了血液干细胞中的硬连续的异质性

获取原文
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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.
机译：动机：转录因子与顺式调节元素的组合相互作用通过连续的细胞状态控制动态进展，从而支撑所有美德南开发。因此，CIS-COMMINATION元件的网络模型的构建有可能产生对细胞命运和分化产生的根本洞察力。 Haematopoiesis长期以来担任模型系统，以研究哺乳动物的差异化，但基于实验知情的CIS-COMMIS-COMMITATASTACTASTACTION的建模已经仅限于对相互作用因素的对。在这里，我们已经基于连接11个血液吞咽/祖细胞（HSPC）调节基因的详细顺式调节功能数据的布尔网络模型。结果：尽管其简单明显，但该模型表现出令人惊讶的复杂行为，以便在其布尔州空间中使用强连接的组件和最短路径分析进行绘制。对我们模型的这种分析预测HSPCS显示异构表情模式并具有许多中间状态，可以充当HSPC以实现最终差异化状态的“踩踏石头”。重要的是，需要外部扰动或“触发”以离开干细胞状态，以不同的触发表征成熟到各种不同的谱系中。通过专注于在红细胞分化期间发生的中间状态，我们从我们的模型中预测了GATA1的FLI1的新型负调节，我们通过实验证实因此验证了我们的模型。总之，我们证明，基于实验验证的CIS-COMMICATIONACTACTIASTACTION的先进的哺乳动物监管网络模型使我们能够制作关于控制哺乳动物干细胞分化的转录机制的新颖，实验可测试的假设。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号