GATA2 mitotic bookmarking is required for definitive haematopoiesis

Rita Silvério-Alves, Ilia Kurochkin, Anna Rydström, Camila Vazquez Echegaray, Jakob Haider, Matthew Nicholls, Christina Rode, Louise Thelaus, Aida Yifter Lindgren, Alexandra Gabriela Ferreira, Rafael Brandão, Jonas Larsson, Marella F. T. R. Bruijn, Javier Martin-Gonzalez and Carlos-Filipe Pereira ()
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Rita Silvério-Alves: Lund University, BMC A12
Ilia Kurochkin: Lund University, BMC A12
Anna Rydström: Lund University, BMC A12
Camila Vazquez Echegaray: Lund University, BMC A12
Jakob Haider: Lund University, BMC A12
Matthew Nicholls: University of Oxford
Christina Rode: University of Oxford
Louise Thelaus: Lund University, BMC A12
Aida Yifter Lindgren: Lund University, BMC A12
Alexandra Gabriela Ferreira: Lund University, BMC A12
Rafael Brandão: University of Copenhagen, Blegdamsvej 3B
Jonas Larsson: Lund University, BMC A12
Marella F. T. R. Bruijn: University of Oxford
Javier Martin-Gonzalez: University of Copenhagen, Blegdamsvej 3B
Carlos-Filipe Pereira: Lund University, BMC A12

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40391-x

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