RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis

Research output: Contribution to journalArticle

Authors

  • Richard Ingram
  • Rebecca Hannah
  • Dorothee Müller
  • Deborah Clarke
  • Salam A Assi
  • Michael Lie-A-Ling
  • Laura Noailles
  • M S Vijayabaskar
  • Mengchu Wu
  • Daniel G Tenen
  • David R Westhead
  • Valerie Kouskoff
  • Georges Lacaud
  • Berthold Göttgens

Colleges, School and Institutes

Abstract

Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a Runx1-/- embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies.

Details

Original languageEnglish
Pages (from-to)4318-4333
Number of pages16
JournalThe EMBO journal
Volume31
Issue number22
Early online date12 Oct 2012
Publication statusPublished - 14 Nov 2012

Keywords

  • Cell Fate Decisions, Endothelial–Haematopoietic Transition, Haematopoiesis, RUNX1, Transcriptional Programming Of Chromatin