GATA2 mitotic bookmarking is required for definitive haematopoiesis
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In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.
| Original language | English |
|---|---|
| Article number | 4645 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| Number of pages | 17 |
| ISSN | 2041-1723 |
| DOIs | |
| Publication status | Published - 2023 |
Bibliographical note
Funding Information:
We thank the members of the Cell Reprogramming in Haematopoiesis and Immunity Laboratory for useful discussions. We thank Dr. Sjaak Philipsen (Erasmus MC, Netherlands) for kindly providing the GATA2 deletion constructs, as well as Dr. Gerd Blobel (University of Pennsylvania, USA) for the MD-GATA1 and MDmut -GATA1 plasmids and sequences. We also thank Dame Amanda Fisher (Imperial College London, UK) for her critical input. We thank the Center for Translational Genomics and Clinical Genomics Lund (SciLifeLab) for providing sequencing services and Lund University Bioimaging Center for microscopy assistance. We also thank Lund Stem Cell Center FACS Facility for cell sorting, and the Centre for Comparative Medicine for animal facilities, particularly Rosa-Linda Meza and Sofia Ekbjörn for handling the mouse models used in this study. This project has received funding (C.-F.P.) from the Olle Engkvist Foundation (194-0694), FCT (2022.02338.PTDC) and Plano de Recuperação e Resiliência de Portugal pelo fundo NextGenerationEU (C644865576-00000005). We would like to acknowledge the Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University and Region Skåne for financial support. R.S.-A received funding from the Royal Physiographic Society of Lund. Research in the de Bruijn group was supported by a program in the MRC Molecular Haematology Unit Core award (MC_UU_00016/02). C.V.E. is supported by a Marie Curie postdoctoral fellowship (101067501). R.S.-A and A.G.F. are supported by FCT scholarships with references PD/BD/135725/2018 and SFRH/BD/133233/2017, respectively.
Funding Information:
We thank the members of the Cell Reprogramming in Haematopoiesis and Immunity Laboratory for useful discussions. We thank Dr. Sjaak Philipsen (Erasmus MC, Netherlands) for kindly providing the GATA2 deletion constructs, as well as Dr. Gerd Blobel (University of Pennsylvania, USA) for the MD-GATA1 and MD-GATA1 plasmids and sequences. We also thank Dame Amanda Fisher (Imperial College London, UK) for her critical input. We thank the Center for Translational Genomics and Clinical Genomics Lund (SciLifeLab) for providing sequencing services and Lund University Bioimaging Center for microscopy assistance. We also thank Lund Stem Cell Center FACS Facility for cell sorting, and the Centre for Comparative Medicine for animal facilities, particularly Rosa-Linda Meza and Sofia Ekbjörn for handling the mouse models used in this study. This project has received funding (C.-F.P.) from the Olle Engkvist Foundation (194-0694), FCT (2022.02338.PTDC) and Plano de Recuperação e Resiliência de Portugal pelo fundo NextGenerationEU (C644865576-00000005). We would like to acknowledge the Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University and Region Skåne for financial support. R.S.-A received funding from the Royal Physiographic Society of Lund. Research in the de Bruijn group was supported by a program in the MRC Molecular Haematology Unit Core award (MC_UU_00016/02). C.V.E. is supported by a Marie Curie postdoctoral fellowship (101067501). R.S.-A and A.G.F. are supported by FCT scholarships with references PD/BD/135725/2018 and SFRH/BD/133233/2017, respectively. mut
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