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GATA2 at the mitosis-to-G1 transition is critical for definitive hematopoiesis

Alves, Rita LU ; Haider, Jakob LU ; Thelaus, Louise LU ; Lindgren, Aida ; Ferreira, Gabriela LU orcid ; Rosa, Fábio LU ; Gonzalez, Javier and Pereira, Carlos-Filipe LU orcid (2021) 2021 Virtual Annual Scientific Meeting of the ISEH - International Society for Experimental Hematology: ISEH 50th Annual Meeting In Experimental Hematology 100(Suppl). p.35-35
Abstract
In mitosis, transcription factors (TFs) and RNA polymerase disperse across the cytoplasm leading to transcriptional silencing, but some TFs are retained on condensed chromatin and mark genomic sites, a mechanism termed mitotic bookmarking. In pluripotent and differentiated cells this mechanism is important for pluripotency maintenance, cell reprogramming and lineage inheritance. However, the role of bookmarking in adult stem cells or in an in vivo system is yet to be addressed. Hematopoietic stem cells undergo drastic changes in cell cycle during development while balancing self-renewal and differentiation, suggesting a possible role for bookmarking.

Here, we first addressed the mitotic retention capacity of the hemogenic TFs... (More)
In mitosis, transcription factors (TFs) and RNA polymerase disperse across the cytoplasm leading to transcriptional silencing, but some TFs are retained on condensed chromatin and mark genomic sites, a mechanism termed mitotic bookmarking. In pluripotent and differentiated cells this mechanism is important for pluripotency maintenance, cell reprogramming and lineage inheritance. However, the role of bookmarking in adult stem cells or in an in vivo system is yet to be addressed. Hematopoietic stem cells undergo drastic changes in cell cycle during development while balancing self-renewal and differentiation, suggesting a possible role for bookmarking.

Here, we first addressed the mitotic retention capacity of the hemogenic TFs GATA2, GFI1B and FOS. We show that GATA2 remains bound to chromatin at all phases of cell cycle, as opposed to GFI1B and FOS. The C-terminal zinc finger (C-ZF) and the nuclear localization signal domains are required for GATA2 mitotic binding. Point mutations in the C-ZF associated with leukemia also impact GATA2 retention. To address the role of GATA2-mediated mitotic bookmarking, we have fused GATA2 to a mitosis degradation (MD) domain, which promotes protein destruction at the mitosis-to-G1 transition (M-G1). Degradation of GATA2 at M-G1 impacts the reprogramming of human fibroblasts to hemogenic cells. To address the role of GATA2 at M-G1 in vivo, we have generated a mouse model with the MD domain inserted upstream the Gata2 gene. Remarkably, homozygous mice are lethal, phenocopying Gata2 null mice which die at the onset of definitive hematopoiesis, showing a deficit in hematopoietic stem and progenitor cells.

These findings implicate GATA2 as a mitotic bookmarking factor and its critical role at M-G1 for definitive hematopoiesis. Overall, our study highlights a dependency on mitotic bookmarkers for in vivo lineage commitment. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
100
issue
Suppl
pages
35 - 35
publisher
Elsevier
conference name
2021 Virtual Annual Scientific Meeting of the ISEH - International Society for Experimental Hematology: ISEH 50th Annual Meeting
conference dates
2021-08-25 - 2021-08-28
ISSN
1873-2399
DOI
10.1016/j.exphem.2021.12.381
language
English
LU publication?
yes
id
ed1132b5-d1c4-49db-bf1b-ba5fa1aba5ed
date added to LUP
2023-08-10 21:26:53
date last changed
2023-08-14 14:50:09
@misc{ed1132b5-d1c4-49db-bf1b-ba5fa1aba5ed,
  abstract     = {{In mitosis, transcription factors (TFs) and RNA polymerase disperse across the cytoplasm leading to transcriptional silencing, but some TFs are retained on condensed chromatin and mark genomic sites, a mechanism termed mitotic bookmarking. In pluripotent and differentiated cells this mechanism is important for pluripotency maintenance, cell reprogramming and lineage inheritance. However, the role of bookmarking in adult stem cells or in an in vivo system is yet to be addressed. Hematopoietic stem cells undergo drastic changes in cell cycle during development while balancing self-renewal and differentiation, suggesting a possible role for bookmarking.<br/><br/>Here, we first addressed the mitotic retention capacity of the hemogenic TFs GATA2, GFI1B and FOS. We show that GATA2 remains bound to chromatin at all phases of cell cycle, as opposed to GFI1B and FOS. The C-terminal zinc finger (C-ZF) and the nuclear localization signal domains are required for GATA2 mitotic binding. Point mutations in the C-ZF associated with leukemia also impact GATA2 retention. To address the role of GATA2-mediated mitotic bookmarking, we have fused GATA2 to a mitosis degradation (MD) domain, which promotes protein destruction at the mitosis-to-G1 transition (M-G1). Degradation of GATA2 at M-G1 impacts the reprogramming of human fibroblasts to hemogenic cells. To address the role of GATA2 at M-G1 in vivo, we have generated a mouse model with the MD domain inserted upstream the Gata2 gene. Remarkably, homozygous mice are lethal, phenocopying Gata2 null mice which die at the onset of definitive hematopoiesis, showing a deficit in hematopoietic stem and progenitor cells.<br/><br/>These findings implicate GATA2 as a mitotic bookmarking factor and its critical role at M-G1 for definitive hematopoiesis. Overall, our study highlights a dependency on mitotic bookmarkers for in vivo lineage commitment.}},
  author       = {{Alves, Rita and Haider, Jakob and Thelaus, Louise and Lindgren, Aida and Ferreira, Gabriela and Rosa, Fábio and Gonzalez, Javier and Pereira, Carlos-Filipe}},
  issn         = {{1873-2399}},
  language     = {{eng}},
  month        = {{08}},
  note         = {{Conference Abstract}},
  number       = {{Suppl}},
  pages        = {{35--35}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{GATA2 at the mitosis-to-G1 transition is critical for definitive hematopoiesis}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2021.12.381}},
  doi          = {{10.1016/j.exphem.2021.12.381}},
  volume       = {{100}},
  year         = {{2021}},
}