The control of transcriptional memory by stable mitotic bookmarking
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PROVIDER: PRJNA749612 | ENA |
REPOSITORIES: ENA
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Project description:To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is thought to be mediated, in part, by mitotic bookmarking by transcription factors (TF). However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses of Drosophila early embryos, we provide evidence that the pioneer-like transcription factor GAF acts as stable mitotic bookmarker during zygotic genome activation. We report that GAF remains associated to a large fraction of its interphase targets (37%). Mitotically-bound loci include cis-regulatory sequences of key developmental genes, with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and a subset is also mitotically bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we provide evidence that GAF binding establishes competence for rapid activation upon mitotic exit.
2022-02-25 | GSE180812 | GEO
Project description:Mitotic bookmarking transcription factors (TFs) are thought to mediate rapid and accurate post-mitotic gene reactivation. However, the loss of individual bookmarking TFs often leads to the deregulation of only a small proportion of their mitotic targets, raising doubts on the significance and importance of their bookmarking function. Here, we used targeted proteomics of the mitotic bookmarking TF ESRRB, an orphan nuclear receptor, to discover an unexpected redundancy among members of the protein superfamily of nuclear receptors. Focusing on the nuclear receptor NR5A2, which together with ESRRB is essential in maintaining pluripotency in mouse embryonic stem cells, we demonstrate conjoint bookmarking activity of both factors on promoters and enhancers of a large fraction of active genes, particularly the most rapidly and strongly reactivated ones. Upon fast and simultaneous degradation of both factors during mitotic exit, hundreds of mitotic targets of ESRRB/NR5A2, including key players of the pluripotency network, display attenuated transcriptional reactivation. We propose that redundancy in mitotic bookmarking TFs, especially nuclear receptors, confers robustness to the reestablishment of gene regulatory networks after mitosis.
2022-12-06 | GSE220253 | GEO
Project description:Mitotic bookmarking transcription factors (TFs) are thought to mediate rapid and accurate post-mitotic gene reactivation. However, the loss of individual bookmarking TFs often leads to the deregulation of only a small proportion of their mitotic targets, raising doubts on the significance and importance of their bookmarking function. Here, we used targeted proteomics of the mitotic bookmarking TF ESRRB, an orphan nuclear receptor, to discover an unexpected redundancy among members of the protein superfamily of nuclear receptors. Focusing on the nuclear receptor NR5A2, which together with ESRRB is essential in maintaining pluripotency in mouse embryonic stem cells, we demonstrate conjoint bookmarking activity of both factors on promoters and enhancers of a large fraction of active genes, particularly the most rapidly and strongly reactivated ones. Upon fast and simultaneous degradation of both factors during mitotic exit, hundreds of mitotic targets of ESRRB/NR5A2, including key players of the pluripotency network, display attenuated transcriptional reactivation. We propose that redundancy in mitotic bookmarking TFs, especially nuclear receptors, confers robustness to the reestablishment of gene regulatory networks after mitosis.
2023-11-20 | PXD038950 | Pride
Project description:For cells to initiate and sustain a differentiated state, it is necessary that a “memory” of this state is transmitted through mitosis to the daughter cells. Mammalian SWItch/ Sucrose Non- Fermentable (SWI/SNF) complexes, also called Brg1/ Brg- associated factors (BAF), control cell identity by modulating chromatin architecture to regulate gene expression, but whether they participate in cell fate memory is unclear. Here, we provide evidence that subunits of SWI/SNF act as mitotic bookmarks to safeguard cell identity during cell division. The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but bound on promoters during mitosis and we show that this binding is required for appropriate reactivation of bound genes after mitotic exit. Ablation of SMARCE1 during a single mitosis in mouse embryonic stem cells is sufficient to disrupt gene expression, impair the occupancy of several established bookmarks at a subset of their targets, and cause aberrant neural differentiation. Thus, SWI/SNF subunit SMARCE1 plays a mitotic bookmarking role and is essential for heritable epigenetic fidelity during transcriptional reprogramming.
2023-03-18 | GSE189563 | GEO
Project description:A stable mode of bookmarking by TBP recruits RNAPolymerase II to mitotic chromosomes
| PRJNA432429 | ENA
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
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 | GSE221691 | GEO
Project description:One critical task in pluripotent reprogramming is to erase the somatic transcriptional program of starting cells. No strategy or theory exists for achieving erasure of somatic gene expression memory. Here, we present a proof-of-principle strategy in which reprogramming to pluripotency is facilitated by small molecules that erase somatic cell transcription memory. We show that mild chemical targeting of the acetyllysine-binding pockets of the BET bromodomains, the transcriptional bookmarking domains, robustly enhances reprogramming. Furthermore, we show that chemical targeting of the transcriptional bookmarking BET bromodomains dramatically downregulates specific somatic gene expression programs in both naïve and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also resulted in loss of fibroblast morphology early in reprograming. In this study, we experimentally demonstrate a concept for cell fate conversion: facilitating the conversion by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory. human BJ cells were treated with JQ1 at 50 nM for 48 hours. Differential expression was compared with DMSO treatment. The same treatments and comparsion were conducted for reprogramming BJ cells, which were transduced with OCT4, SOX2, and KLF4. JQ1iPSC5 is a iPSC (induced pluripotent stem cell) line generated in this study using small molecules JQ1.
2016-08-22 | E-GEOD-75364 | biostudies-arrayexpress
Project description:Genetic and epigenetic changes in mammary epithelial cells facilitate epithelial-to-mesenchymal transition (EMT) which leads to invasion and metastasis. RUNX1 is a phenotypic transcription factor pivotal for maintenance of mammary epithelial phenotype, whose loss leads to EMT. However, the mechanisms by which RUNX1 maintains mammary epithelial phenotype are not known. Here, we report RUNX1-mediated mitotic gene bookmarking as a key epigenetic mechanism through which RUNX1 stabilizes mammary epithelial phenotype by conveying regulatory information for cell proliferation, growth, and identity through successive cell divisions. Immunofluorescence microscopy and chromatin immunoprecipitation with high throughput sequencing of asynchronous, mitotic, and G1 MCF10A breast epithelial cells revealed RUNX1 association with target genes through interphase and mitosis. RUNX1 mitotically bookmarked both RNA Pol and II transcribed genes involved in proliferation, growth, and mammary epithelial phenotype maintenance. Inhibition of RUNX1 DNA binding by a specific small molecule inhibitor led to phenotypic changes, apoptosis, and differential expression of ribosomal RNA as well as protein coding genes (e.g. HES1 and H2AFX) and long non-coding RNA (e.g. NEAT1 and MALAT1) genes involved in cellular phenotype. Together these findings reveal a novel epigenetic regulatory role of RUNX1 in normal-like breast epithelial cells and demonstrate mitotic bookmarking target genes by RUNX1 is necessary to maintain breast epithelial phenotype. Disruption of RUNX1 bookmarking by a pharmacological inhibitor results in initiation of epithelial to mesenchymal transition, an essential first step in the onset of breast cancer.
2020-07-14 | GSE121370 | GEO
Project description:Mitotic bookmarking by CTCF and fast post-mitotic gene reactivation in ES cells
| PRJNA807661 | ENA