WFRF:(Pereira Carlos Filipe)
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GATA2 at the mitosis-to-G1 transition is critical for definitive hematopoiesis
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- Alves, Rita (author)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Cellulär omprogrammering i hematopoes och immunitet,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Cell Reprogramming in Hematopoiesis and Immunity,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,University of Coimbra
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- Haider, Jakob (author)
- University of Applied Sciences Campus Vienna
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- Thelaus, Louise (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Translationell Sepsisforskning,Forskargrupper vid Lunds universitet,Heparinbindande protein inom thoraxkirurgi,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Translational Sepsis research,Lund University Research Groups,Heparin bindning protein in cardiothoracic surgery
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- (creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
- In: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 100:Suppl, s. 35-35
- Conference paper (peer-reviewed)
Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
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