Swiers Gemma, Patient Roger, Loose Matthew
Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Dev Biol. 2006 Jun 15;294(2):525-40. doi: 10.1016/j.ydbio.2006.02.051. Epub 2006 Apr 19.
Erythroid cell production results from passage through cellular hierarchies dependent on differential gene expression under the control of transcription factors responsive to changing niches. We have constructed Genetic Regulatory Networks (GRNs) describing this process, based predominantly on mouse data. Regulatory network motifs identified in E. coli and yeast GRNs are found in combination in these GRNs. Feed-forward motifs with autoregulation generate forward momentum and also control its rate, which is at its lowest in hematopoietic stem cells (HSCs). The simultaneous requirement for multiple regulators in multi-input motifs (MIMs) provides tight control over expression of target genes. Combinations of MIMs, exemplified by the SCL/LMO2 complexes, which have variable content and binding sites, explain how individual regulators can have different targets in HSCs and erythroid cells and possibly also how HSCs maintain stem cell functions while expressing lineage-affiliated genes at low level, so-called multi-lineage priming. MIMs combined with cross-antagonism describe the relationship between PU.1 and GATA-1 and between two of their target genes, Fli-1 and EKLF, with victory for GATA-1 and EKLF leading to erythroid lineage specification. These GRNs are useful repositories for current regulatory information, are accessible in interactive form via the internet, enable the consequences of perturbation to be predicted, and can act as seed networks to organize the rapidly accumulating microarray data.
红细胞生成源于细胞通过细胞层级结构，该过程依赖于在对变化的微环境有反应的转录因子控制下的差异基因表达。我们主要基于小鼠数据构建了描述这一过程的基因调控网络（GRN）。在大肠杆菌和酵母GRN中鉴定出的调控网络基序在这些GRN中组合出现。具有自动调节功能的前馈基序产生向前的动力并控制其速率，这一速率在造血干细胞（HSC）中最低。多输入基序（MIM）中对多种调节因子的同时需求对靶基因的表达提供了严格控制。以SCL/LMO2复合物为例的MIM组合，其具有可变的成分和结合位点，解释了单个调节因子如何在HSC和红细胞中具有不同的靶标，也可能解释了HSC如何在低水平表达谱系相关基因的同时维持干细胞功能，即所谓的多谱系启动。与交叉拮抗相结合的MIM描述了PU.1和GATA-1之间以及它们两个靶基因Fli-1和EKLF之间的关系，GATA-1和EKLF的胜利导致红细胞谱系特化。这些GRN是当前调控信息的有用储存库，可通过互联网以交互式形式访问，能够预测扰动的后果，并且可以作为种子网络来组织快速积累的微阵列数据。
