Cell fate determination is associated with changes in competing transcriptional units in the human GATA1 and GATA2 lineage-determining transcription factors

The GATA1 and GATA2 transcription factors play a central role in early cell fate decisions in hematopoietic progenitor cells. Although the switch from GATA2 to GATA1 occupancy at GATA-binding sites in erythroblast-specific genes has been extensively studied, the underlying molecular mechanisms controlling this switch are not fully elucidated. An antisense promoter in the 5 region of the GATA2 gene produces a long non-coding RNA that has been shown to affect GATA2 transcription and erythroblast differentiation. The recent identification of an antisense promoter in the first intron of the GATA1 gene indicates that similar promoter competition mechanisms operate in these genes, potentially controlling GATA1/GATA2 levels in a probabilistic manner. In the current study we perform a comprehensive evaluation of GATA1 and GATA2 transcripts in human CD34+ progenitors either freshly isolated or differentiated in vitro and the human leukemia cell lines K562 and HL60. The ratio of competing sense and antisense transcripts varied significantly with differentiation status, suggesting that promoter competition controls cell fate decisions. Treatment of HL60 cells with differentiating agents resulted in significant changes in the ratio of GATA2 sense to antisense promoter activity, in agreement with previous results showing that sense and antisense transcription are associated with distinct cellular phenotypes.