RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis.
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.
Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Monika
M
Lichtinger
Richard
R
Ingram
Rebecca
R
Hannah
Dorothee
D
Müller
Deborah
D
Clarke
Salam A
SA
Assi
Michael
M
Lie-A-Ling
Laura
L
Noailles
M S
MS
Vijayabaskar
Mengchu
M
Wu
Daniel G
DG
Tenen
David R
DR
Westhead
Valerie
V
Kouskoff
Georges
G
Lacaud
Berthold
B
Göttgens
Constanze
C
Bonifer
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D014157:Transcription Factors / Q000502:physiology
D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; C493726:Runx1 protein, mouse; D014157:Transcription Factors