Gene regulation by RUNX1 in the absence of consensus sequences

AM Woodworth
2020
Runt-related transcription factor 1 (RUNX1) is a transcription factor that has an important role in haematopoietic cell development and function and is frequently disrupted in leukaemia. RUNX1 is commonly described as a sequence-specific DNA binding factor which recognises the consensus sequence TG(T/C)GGT in the promoter and enhancer regions of its target genes to affect changes in gene expression. However, the advent of techniques to study DNA-protein interactions on a genome-wide scale has
more » ... me-wide scale has provided the opportunity to re-assess RUNX1 localisation and function, and this analysis suggests that the classical model of RUNX1 function is incomplete. By fully understanding the mechanisms by which RUNX1 maintains its target gene expression profiles under normal cellular conditions, insights into disrupted function can be gained and interventions can be developed. Analysis of publicly available RUNX1 ChIP-Seq data determined that the majority of RUNX1 binding in haematopoietic cells occurs outside of gene promoter regions, in intergenic or intronic regions. Furthermore, approximately one fifth of all RUNX1-DNA binding sites on a genome-wide scale were not associated with a canonical consensus sequence, and this was particularly prevalent in promoter regions, with almost half of RUNX1 binding in promoter regions occurring in the absence of consensus sequences. This suggests that recruitment of RUNX1 to gene targets occurs through multiple mechanisms and raises the possibility that it may function differently depending on its location and mode of recruitment. Similar results were obtained for localisation of the RUNX1 fusion protein RUNX1-ETO, the product of a common chromosomal translocation in leukaemia. This data set was used to investigate the different modes of binding and action of RUNX1 with the aim of establishing whether binding in the absence of consensus sequences constitutes a novel mechanism of RUNX1 binding and if genes regulated in this way respond differently to RUNX1 disruption. This study identified biol [...]
doi:10.25959/100.00035253 fatcat:hy6ku4ilwfanbp5yudl25n6chq