Abstract
Haematopoietic cells arise from endothelial cells within the dorsal aorta of the embryo via a process called the endothelial-haematopoietic transition (EHT). This process crucially depends on the transcription factor RUNX1 which rapidly activates the expression of genes essential for haematopoietic development. Using an inducible version of RUNX1 in a mouse embryonic stem cell differentiation model we showed that prior to the EHT, haematopoietic genes are primed by the binding of the transcription factor FLI1. Once expressed, RUNX1 relocates FLI1 towards its binding sites. However, the nature of the transcription factor assemblies recruited by RUNX1 to reshape the chromatin landscape and initiate mRNA synthesis are unclear. Here, we performed genome-wide analyses of RUNX1-dependent binding of factors associated with transcription elongation to address this question. We demonstrate that RUNX1 induction moves FLI1 from distal ETS/GATA sites to RUNX1/ETS sites and recruits the basal transcription factors CDK9, BRD4, the Mediator complex and the looping factor LDB1. Our study explains how the expression of a single transcription factor can drive rapid and replication independent transitions in cellular shape which are widely observed in development and disease.
Highlights
Using an established model of Embryonic Stem Cell (ESC) differentiation we previously examined the role of RUNX1 in the onset of a haematopoietic transcriptional program
We used the inducible RUNX1 (iRUNX1) system to dissect, at the global level, how RUNX1 orchestrates the formation of transcription factor complexes and Polymerase II (Pol II) recruitment to drive the transcriptional processes that underlie the endothelial-haematopoietic transition (EHT)
Using an inducible RUNX1 ES cell line we previously found that RUNX1 orchestrates the relocation of the transcription factors FLI1 and SCL/TAL1 during the EHT13
Summary
Using an established model of Embryonic Stem Cell (ESC) differentiation we previously examined the role of RUNX1 in the onset of a haematopoietic transcriptional program. We used the iRUNX1 system to dissect, at the global level, how RUNX1 orchestrates the formation of transcription factor complexes and Pol II recruitment to drive the transcriptional processes that underlie the EHT. We show that after induction, genome-wide redistribution of TF complexes by RUNX1 is coupled with increased enrichment of CDK9 at distal sites, the onset of transcription of genes essential for haematopoietic development and increased deposition of the H3K79me[2] mark on histones as a marker for transcriptional elongation. Our data show a direct requirement for RUNX1 to recruit factors associated with transcriptional elongation and to orchestrate the reorganisation of interacting transcription factor complexes, facilitating a permissive environment for the rapid activation of genes essential for the EHT
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