The RUNX1 transcription factor is expressed in a range of cell types, but most notably regulates cellular differentiation and commitment vital for haematopoietic development as well as the function of mature haematopoietic cells. Not surprisingly then, RUNX1 disruption contributes to the development of leukaemia and occurs in approximately 10% of leukaemia cases. Characterisation of RUNX1 target genes has demonstrated that RUNX1 can regulate gene expression by binding to a well-defined consensus motif, TG(T/C)GGT, or variations on this, located in gene promoters or enhancers.
By analysing publicly available ChIP-Seq datasets, we demonstrate that a consensus motif is associated with only 79% of genomic binding of RUNX1. Interestingly, the distribution of non-consensus sequence binding is disproportionally distributed throughout the genome. Only 20% of genomic binding is associated with promoter regions, with 43% of this binding occurring in the absence of a consensus motif. By contrast, approximately 85% of RUNX1 recruitment at non-promoter regions is associated with consensus motifs. Ingenuity Pathway Analysis of genes with RUNX1 bound promoters has revealed the existence of biological pathways in which the RUNX1 binding events are either “all consensus motif present” or “all consensus motif absent”. Interestingly, these pathways which contain exclusively motif present or motif absent binding make up more than half (59%) of the pathways identified as being enriched for RUNX1 bound genes. Analysis of candidate genes is revealing that distinct mechanisms are involved in the regulation of target genes, which is dependent on the presence or absence of a consensus motif.
Our analysis therefore indicates that consensus sequence-driven recruitment does not explain a large proportion of the genome-wide occupancy of RUNX1, and suggests that fundamentally distinct mechanisms exist to recruit RUNX1 to target genes. The clustering of differently regulated genes into distinct biological pathways raises the possibility that these distinct mechanisms may be important in regulating different cellular processes.