Cell cycle states of pluripotent cells dictate lineage decisions
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ABSTRACT:
PROVIDER: PRJNA738859 | ENA |
REPOSITORIES: ENA
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Project description:Cell cycle and differentiation decisions are tightly linked; however, the underlying principles that drive these decisions are not fully understood. Here, we combined cell-cycle reporter system and single-cell RNA-seq profiling, to study the transcriptomes of mouse embryonic stem cells (ESCs) in the context of cell cycle states and differentiation. By applying a retinoic acid-based differentiation protocol we show that only cells in the G2/M phase are capable of differentiating into extraembryonic endoderm cells (XENs), whereas cells in the G1 phase predominantly produce epiblast stem cells (EpiSCs). Mechanistically, we show that Esrrb is a potent XEN state inducer as it is predominantly upregulated during G2/M phase, and cells engineered to overexpress Esrrb during G1 phase forced the cells to become XENs. Interestingly, this phenomenon is unique to the pluripotency ground state as sorting cells after 48 hours of differentiation resulted in a cell cycle-independent differentiation decisions. Cells in both G1 and G2/M phases contributed equally to EpiSC and XEN cellular lineages. Taken together, this study reveals an important functional link between cell-cycle states of pluripotent cells and lineage decisions, emphasizing the regulatory role of cell cycle during exit from pluripotency and can be further expand our understanding of early differentiation events.
2022-05-19 | GSE178390 | GEO
Project description:DNA damage activates diverse cellular responses – either protective or deleterious –that ultimately promote or inhibit proliferation. How the distinct responses conferring crucial cell fate decisions are chosen is unclear. Using a systems approach, we demonstrate that the dynamic features of Atm dependent DNA double-strand break (DSB) signalling response dictate cellular outcome. Combining temporal phosphoproteome and nascent transcriptome analyses after low or high DNA-damage-load, we discovered that some responses, such as Tp53 activation, have an activation threshold and others arise independently of DNA-damage-load. Using DSB repair deficient cells, we show that persistent DSBs alter the kinetics – but not the amplitude – of Atm signalling. Thus, we demonstrate that pathway choices are dictated by the signalling dynamics and hence cell fate decisions are responsive to DNA-damage-load and repair capacity of the cells.
2023-01-18 | PXD013620 | Pride
Project description:Sox7 regulates lineage decisions in cardiovascular progenitor cells
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Project description:ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development
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Project description:The hematopoietic system relies on the dynamic control of transcriptional regulatory networks, yet our understanding of the mechanisms that dictate the generation of diverse, mature progeny from hematopoietic stem cells are continuously evolving. Transposable elements (TEs) in the human genome and their chromatin regulators are implicated to sculpt the regulatory networks of immune cells. We systematically dissected the contributions of TEs to human hematopoiesis and demonstrated that TEs play instructive roles in lineage determination from primary human hematopoietic stem and progenitor cells. We built a comprehensive, cell type resolved enhancer-gene atlas of the human hematopoietic system and identified that TEs contribute to cell type and lineage specific enhancers. TEs exhibited dynamic transcription during lymphoid differentiation. Chemical and genetic perturbation of regulators of heterochromatin within primary human hematopoietic stem and progenitor cells derepressed TEs and elicited lineage biases during lymphoid differentiation. Knockout of the H3K9 methyltransferase EHMT1 or the heterochromatin adaptor protein TRIM28 resulted in lineage skewing to natural killer (NK) cells at the expense of B and T cells. Single cell RNA and ATAC-sequencing revealed that lineage skewing manifested early within hematopoietic progenitors. Further, knockout of TRIM28 or EHMT1 generated NK cells with distinct effector functions, where loss of TRIM28 resulted in enhanced IFN-ɣ producing NK cells and loss of EHMT1 enhanced the generation of CD16+ NK cells. Distinct TE families were epigenetically derepressed in EHMT1 versus TRIM28 knockout NK cells, yet enriched for NK-relevant transcription factor motifs. Modulation of heterochromatin machinery underscores the role of TEs in human hematopoietic differentiation and enables novel approaches to derive diverse NK cell subtypes for adoptive cell therapies.
2024-05-31 | GSE232103 | GEO
Project description:The hematopoietic system relies on the dynamic control of transcriptional regulatory networks, yet our understanding of the mechanisms that dictate the generation of diverse, mature progeny from hematopoietic stem cells are continuously evolving. Transposable elements (TEs) in the human genome and their chromatin regulators are implicated to sculpt the regulatory networks of immune cells. We systematically dissected the contributions of TEs to human hematopoiesis and demonstrated that TEs play instructive roles in lineage determination from primary human hematopoietic stem and progenitor cells. We built a comprehensive, cell type resolved enhancer-gene atlas of the human hematopoietic system and identified that TEs contribute to cell type and lineage specific enhancers. TEs exhibited dynamic transcription during lymphoid differentiation. Chemical and genetic perturbation of regulators of heterochromatin within primary human hematopoietic stem and progenitor cells derepressed TEs and elicited lineage biases during lymphoid differentiation. Knockout of the H3K9 methyltransferase EHMT1 or the heterochromatin adaptor protein TRIM28 resulted in lineage skewing to natural killer (NK) cells at the expense of B and T cells. Single cell RNA and ATAC-sequencing revealed that lineage skewing manifested early within hematopoietic progenitors. Further, knockout of TRIM28 or EHMT1 generated NK cells with distinct effector functions, where loss of TRIM28 resulted in enhanced IFN-ɣ producing NK cells and loss of EHMT1 enhanced the generation of CD16+ NK cells. Distinct TE families were epigenetically derepressed in EHMT1 versus TRIM28 knockout NK cells, yet enriched for NK-relevant transcription factor motifs. Modulation of heterochromatin machinery underscores the role of TEs in human hematopoietic differentiation and enables novel approaches to derive diverse NK cell subtypes for adoptive cell therapies.
2024-05-31 | GSE232104 | GEO
Project description:Differentiation of mammalian pluripotent cells involves large-scale changes in transcription and, among the molecules that orchestrate these changes, chromatin remodellers are essential to initiate, establish and maintain a new gene regulatory network. The NuRD complex is a highly conserved chromatin remodeller which fine-tunes gene expression in embryonic stem cells. While the function of NuRD in mouse pluripotent cells has been well defined, no study yet has defined NuRD function in human pluripotent cells. We investigated the structure and function of NuRD in human induced pluripotent stem cells (hiPSCs). Using immunoprecipitation followed by mass-spectrometry in hiPSCs and in naive or primed mouse pluripotent stem cells, we find that NuRD structure and biochemical interactors are generally conserved. Using RNA sequencing, we find that, whereas in mouse primed stem cells and in mouse naive ES cells, NuRD is required for an appropriate level of transcriptional response to differentiation signals, hiPSCs require NuRD to initiate these responses. This difference indicates that mouse and human cells interpret and respond to induction of differentiation differently.
2020-05-04 | PXD016967 | Pride
Project description:The hematopoietic system relies on the dynamic control of transcriptional regulatory networks, yet our understanding of the mechanisms that dictate the generation of diverse, mature progeny from hematopoietic stem cells are continuously evolving. Transposable elements (TEs) in the human genome and their chromatin regulators are implicated to sculpt the regulatory networks of immune cells. We systematically dissected the contributions of TEs to human hematopoiesis and demonstrated that TEs play instructive roles in lineage determination from primary human hematopoietic stem and progenitor cells. We built a comprehensive, cell type resolved enhancer-gene atlas of the human hematopoietic system and identified that TEs contribute to cell type and lineage specific enhancers. TEs exhibited dynamic transcription during lymphoid differentiation. Chemical and genetic perturbation of regulators of heterochromatin within primary human hematopoietic stem and progenitor cells derepressed TEs and elicited lineage biases during lymphoid differentiation. Knockout of the H3K9 methyltransferase EHMT1 or the heterochromatin adaptor protein TRIM28 resulted in lineage skewing to natural killer (NK) cells at the expense of B and T cells. Single cell RNA and ATAC-sequencing revealed that lineage skewing manifested early within hematopoietic progenitors. Further, knockout of TRIM28 or EHMT1 generated NK cells with distinct effector functions, where loss of TRIM28 resulted in enhanced IFN-ɣ producing NK cells and loss of EHMT1 enhanced the generation of CD16+ NK cells. Distinct TE families were epigenetically derepressed in EHMT1 versus TRIM28 knockout NK cells, yet enriched for NK-relevant transcription factor motifs. Modulation of heterochromatin machinery underscores the role of TEs in human hematopoietic differentiation and enables novel approaches to derive diverse NK cell subtypes for adoptive cell therapies.
2024-05-31 | GSE232102 | GEO
Project description:The hematopoietic system relies on the dynamic control of transcriptional regulatory networks, yet our understanding of the mechanisms that dictate the generation of diverse, mature progeny from hematopoietic stem cells are continuously evolving. Transposable elements (TEs) in the human genome and their chromatin regulators are implicated to sculpt the regulatory networks of immune cells. We systematically dissected the contributions of TEs to human hematopoiesis and demonstrated that TEs play instructive roles in lineage determination from primary human hematopoietic stem and progenitor cells. We built a comprehensive, cell type resolved enhancer-gene atlas of the human hematopoietic system and identified that TEs contribute to cell type and lineage specific enhancers. TEs exhibited dynamic transcription during lymphoid differentiation. Chemical and genetic perturbation of regulators of heterochromatin within primary human hematopoietic stem and progenitor cells derepressed TEs and elicited lineage biases during lymphoid differentiation. Knockout of the H3K9 methyltransferase EHMT1 or the heterochromatin adaptor protein TRIM28 resulted in lineage skewing to natural killer (NK) cells at the expense of B and T cells. Single cell RNA and ATAC-sequencing revealed that lineage skewing manifested early within hematopoietic progenitors. Further, knockout of TRIM28 or EHMT1 generated NK cells with distinct effector functions, where loss of TRIM28 resulted in enhanced IFN-ɣ producing NK cells and loss of EHMT1 enhanced the generation of CD16+ NK cells. Distinct TE families were epigenetically derepressed in EHMT1 versus TRIM28 knockout NK cells, yet enriched for NK-relevant transcription factor motifs. Modulation of heterochromatin machinery underscores the role of TEs in human hematopoietic differentiation and enables novel approaches to derive diverse NK cell subtypes for adoptive cell therapies.
2024-05-31 | GSE232101 | GEO
Project description: Not available
| S-EPMC4926280 | biostudies-literature