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GATA2 mitotic bookmarking is required for definitive hematopoiesis [scRNA-seq]

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221691 | GEO | 2023/06/27

REPOSITORIES: GEO

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GATA2 mitotic bookmarking is required for definitive haematopoiesis [ChIP-seq]

Project description: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.

2023-06-27 | GSE207551 | GEO

GATA2 mitotic bookmarking is required for definitive haematopoiesis [ChIP-seq]

Project description:GATA2 mitotic bookmarking is required for definitive haematopoiesis [ChIP-seq]

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Interrogating histone acetylation and BRD4 as mitotic bookmarks of transcription [Histones]

Project description:Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with novel data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger”. Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis.

2019-04-10 | GSE128161 | GEO

Interrogating histone acetylation and BRD4 as mitotic bookmarks of transcription [TFs]

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GATA2 mitotic bookmarking is required for definitive hematopoiesis [scRNA-seq]

Project description:GATA2 mitotic bookmarking is required for definitive hematopoiesis [scRNA-seq]

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Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic co-culture

Project description:Previous work demonstrates an induction of definitive hematopoiesis from human dermal fibroblasts (HDFs) after transduction with the transcription factors (TFs) GATA2, GFI1B, and FOS. To improve the yield and function of the derived hematopoietic cells, TF screening identified GFI1 as a causative factor in hematopoietic cell expansion with in vitro and in vivo functional capacity.

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Project description:Following cell division, genomes must reactivate gene expression patterns that reflect the identity of the cell. Here, we use PRO-seq to examine the mechanisms that reestablish transcription patterns after mitosis. We uncover regulation of the transcription cycle at multiple steps including initiation, promoter-proximal pause positioning and escape, poly-A site cleavage and termination during the mitotic-G1 transition. During mitosis, RNA polymerase activity is retained at initiation sites, albeit shifted in position relative to non-mitotic cells. This activity is strongly linked to maintenance of local chromatin architecture during mitosis and is more predictive of rapid gene reactivation than histone modifications previously associated with bookmarking. These molecular bookmarks, combined with sequence-specific transcription factors, direct expression of select cell growth and cell specific genes during mitosis followed by reactivation of functional gene groups with distinct kinetics after mitosis. This study details how dynamic regulation of transcription at multiple steps contributes to gene expression during the cell cycle.

2022-04-15 | GSE179576 | GEO

Analysis of factors bound to native metaphase ESC chromosomes following purification by flow cytometry

Project description:Stem cells are able to self-renew and also generate differentiated progeny. How gene expression patterns are transmitted through mitosis remains unresolved. Conventional studies have relied upon rigorous cell-cycle-stage synchronisation to find factors in mitotic lysates that could ‘bookmark’ the genome. Here we use an alternative approach, purifying native-unfixed mitotic chromosomes from different cell types using flow cytometry and directly identifying chromosome-bound proteins by LC-MS/MS. This revealed a rich profile of pluripotency- and lineage-specific transcription factors that remained bound to mitotic chromosomes in pluripotent ESCs and lymphocytes, as well as factors implicated in chromosome condensation, architecture and gene silencing. Removal of DNA methylation, PRC2 activity, or in situ cleavage of cohesin, each resulted in the reduced compaction of mitotic chromosomes. These data provide a comprehensive catalogue of bookmarking factors in pluripotent versus lineage-restricted cells and demonstrate an expected duality of function by candidates in regulating both gene expression and mitotic chromosome structure.

2020-06-15 | PXD015251 | Pride

Stem cell regulatory elements remain bookmarked by selected transcription factors and epigenetic marks during mitosis

Project description:Purpose: We investigated the existence, nature and significance of mitotic bookmarking of Klf4, Oct4, Sox2 (KOS) and H3K27ac in mouse ESCs. Methods: DNA-binding/epigenetic profiles of KOS and H3K27ac on asynchronous and mitotic chromatin were generated by deep sequencing following chromatin immunoprecipitation, in replicates. Results: KOS and H3K27ac are largely maintained on mitotic chromatin. KOS bookmark critical stem cell regulatory elements during mitosis. H3K27 acetylation during mitosis is highly retained on promoters of cell cycle and homeostasis related genes and enhancers of genes important for any given cell identity. Conclusions: The extensive mitotic occupancy that we observed is in agreement with a recent study that proposes that TF retention on mitotic chromatin may be a much broader phenomenon than previously appreciated. Bobbie Pelham-Webb is supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. Additionally, this work was funded by the NIH Director s New Innovator Award ( DP2DA043813 ) to Effie Apostolou.

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