SCL, GATA-1, GATA-2 and GATA-3 encode lineage restricted haemopoietic transcription factors. We have previously shown that SCL, GATA-1 and GATA-2 are expressed in multipotent progenitors prior to lineage commitment, but are down-regulated during granulocyte/monocyte differentiation. The phenomenon of gene extinction in cell hybrids may reveal negative regulatory mechanisms operating during normal differentiation. We have therefore analysed the regulation of SCL, GATA-1, GATA-2 and GATA-3 in cell hybrids formed by the fusion of cell lines representing different haemopoietic lineages. Expression of GATA-3 was extinguished in both human and murine erythroid x T cell hybrids, an observation which suggests that erythroid cells contain factors capable of repressing GATA-3 expression. By contrast expression of SCL, GATA-1 and GATA-2 was not extinguished in erythroid x T or in erythroid x B cell hybrids. These data suggest that T cells and B cells do not contain trans-acting factors capable of down-regulating expression of SCL, GATA-1 or GATA-2, and therefore raise the possibility that a 'hit and run' mechanism may repress these genes during normal haemopoiesis. HpaII sites within the SCL promoter were unmethylated in erythroid cells but methylated in T cells. Erythroid x T and erythroid x B cell hybrids contained both methylated and unmethylated SCL promoters, thus implicating a heritable cis-acting mechanism in the regulation of the SCL gene in lymphoid cell lines. These results provide the first analysis of SCL and GATA gene regulation in stable cell hybrids.