Identification and characterisation of 3D transcription networks in vivo

我们的基因组包含大约25,000个基因，必须严格控制这些基因，以便在每个组织中以及在细胞发育或分化的适当时间表达适当的基因子集。尽管我们有许多不同生物体的完整基因组序列，但我们对基因是如何被控制的仍然知之甚少。我们发现，一个基因在细胞核中的位置不是随机的，似乎反映了基因的功能状态。与这一建议更相关的是，我们发现特定的基因亚群在打开时经常聚集在核亚室中。这些被称为转录工厂的小区室含有高浓度的酶，这些酶是将基因转录成mRNA所需的，换句话说，就是开启基因。其产物在生理上有联系的基因（即它们的产物在流水线上以合作的方式工作）必须在同一细胞中协调表达，以产生预期的表型效应。我们发现这些协同表达的基因经常在转录工厂中组合在一起。这些结果表明，每个哺乳动物细胞类型的基因组组织是高度特异性的。基因不仅根据它们的开/关状态来组织，而且还形成协调表达基因的群体或网络，这些基因的产物将在细胞中合作执行特定的生理任务。我们认为这种组织可能是由于许多这些协调表达的基因受相同转录因子调节的可能性。通过聚集在同一工厂中，这些基因可能由于结合位点和转录因子的局部自组织浓度增加而共享相同的转录因子。我们将确定与α和β -珠蛋白基因相关的完整基因网络，这些基因参与血红蛋白的产生。可能许多协同表达基因的调控部分是通过工厂中的合作相互作用实现的。这些结果将极大地扩展我们对基因组功能的认识，这对于理解正常发育和疾病都是至关重要的信息。

Our genomes contain approximately 25,000 genes that must be tightly controlled so that the appropriate subset of genes are expressed in each tissue and at the proper times of cell development or differentiation. Although we have the full genomic sequence for a number of different organisms we still have little idea about how genes are controlled. We have found that a genes location in the nucleus is not random and appears to reflect the functional status of the gene. Of even greater relevance to this proposal, we find that specific sub-groups of genes frequently cluster together in nuclear sub-compartments when they are switched on. These sub-compartments, known as transcription factories contain high concentrations of the enzymes required to transcribe a gene into mRNA, in other words, to turn the gene on. Genes whose products are physiologically linked (i.e. their products work in a cooperative fashion as in an assembly line) must be co-ordinately expressed in the same cell to produce their intended phenotypic effect. We find that these co-ordinately expressed genes frequently group together in transcription factories. These results suggest that the organization of the genome in each mammalian cell-type is highly specific. Genes are organized not only according to their on/off status but also form groups or networks of co-ordinately expressed genes whose products will cooperate to carry out a specific physiological task in the cell. We believe that this organization may be due to the possibility that many of these co-ordinately expressed genes are regulated by the same transcription factors. By clustering together in the same factory these genes may share the same transcription factors due to a self-organizing locally increased concentration of binding sites and transcription factors. We will identify the complete network of genes that frequently associate with the alpha and beta-globin genes, which are involved in hemoglobin production. It may be that regulation of many co-ordinately expressed genes is achieved in part through cooperative interactions in factories. These results will greatly expand our knowledge of how the genome functions which is vitally important information in understanding normal development and disease alike.