Identification and characterisation of 3D transcription networks in vivo

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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.