Gene ecology: A cis-acting gene-to-gene interaction due to the spatial arrangement of genes in chromosomes affects neighbouring transfected c-H-ras expression

A cis-acting interference between gene activities, which occurs when two genes lie on the same DNA strand and have an Intergenic distance less than a defined length, was previously deduced when chromo-somal organizations of various higher eukaryote nuclear genes in clusters were compared. In order to investigate such an interference due to arrangement of genes along chromosomes, we have isolated a few cell lines which possessed (i) human mutated c-H-ras fused with the mouse mammary tumour virus long terminal repeat and (ii) the E. coli xanthine-guanine phosphoribosyltransferase (gpt) gene with the SV40 promoter, on the same or on different DNA strands, separated by a short intergenic distance or unlinked. Since the cancerous phenotype of a cell can be readily identified due to c-H-ras expression, we examined in these cell lines whether continuous c-H-ras expression, induced by dexamethasone, is disturbed through a cis-acting gene-to-gene interaction when the expression of the neighbouring gpt gene is enforced and as a result, the cancerous state of a cell is converted to the 'normal' state. The enforced expression of the neighbouring gpt gene was shown to alter c-H-ras expression, and thus reversible conversion of a cell between cancerous and normal states occurred only when the cell possessed an optimum number of the gene pair, in which both c-H-ras and the gpt gene were on the same DNA strand. This implies that the spatial arrangement of genes in chromosomes plays an important role in the regulation of gene expression in a cluster.