The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David H Dockrell - One of the best experts on this subject based on the ideXlab platform.
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pneumolysin is responsible for differential gene expression and modifications in the Epigenetic Landscape of primary monocyte derived macrophages
Frontiers in Immunology, 2021Co-Authors: Joby Cole, Timothy J Mitchell, Adrienn Angyal, Richard D. Emes, Mark J. Dickman, David H DockrellAbstract:Epigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of Epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the Epigenetic Landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF-α production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that Epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci.
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Pneumolysin is responsible for differential gene expression and modifications in the Epigenetic Landscape of primary monocyte derived macrophages.
2020Co-Authors: Joby Cole, Timothy J Mitchell, Adrienn Angyal, Richard D. Emes, Mark J. Dickman, David H DockrellAbstract:Abstract Epigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of Epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the Epigenetic Landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that Epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci. Author summary Pneumolysin is a toxin that contributes to how Streptococcus pneumoniae, the leading cause of pneumonia, causes disease. In this study, the toxin alters gene expression in immune cells called macrophages, one of the first lines of defence against bacteria at sites of infection. Modulation involved multiple immune responses, including generation of chemical signals coordinating responses in immune cells termed cytokines. In addition, changes were observed in histone proteins that are involved in controlling gene expression in the cell. Pneumolysin reduced early production of the cytokine TNF-α and a medicine vorinostat that modifies these ‘Epigenetic’ histone modifications had a similar affect, suggesting Epigenetic mechanisms contribute to the ability of pneumolysin to reduce immune responses.
Luonan Chen - One of the best experts on this subject based on the ideXlab platform.
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Quantifying Waddington's Epigenetic Landscape: a comparison of single-cell potency measures.
Briefings in bioinformatics, 2018Co-Authors: Jifan Shi, Andrew E. Teschendorff, Weiyan Chen, Luonan ChenAbstract:MOTIVATION Estimating differentiation potency of single cells is a task of great biological and clinical significance, as it may allow identification of normal and cancer stem cell phenotypes. However, very few single-cell potency models have been proposed, and their robustness and reliability across independent studies have not yet been fully assessed. RESULTS Using nine independent single-cell RNA-Seq experiments, we here compare four different single-cell potency models to each other, in their ability to discriminate cells that ought to differ in terms of differentiation potency. Two of the potency models approximate potency via network entropy measures that integrate the single-cell RNA-Seq profile of a cell with a protein interaction network. The comparison between the four models reveals that integration of RNA-Seq data with a protein interaction network dramatically improves the robustness and reliability of single-cell potency estimates. We demonstrate that underlying this robustness is a correlation relationship, according to which high differentiation potency is positively associated with overexpression of network hubs. We further show that overexpressed network hubs are strongly enriched for ribosomal mitochondrial proteins, suggesting that their mRNA levels may provide a universal marker of a cell's potency. Thus, this study provides novel systems-biological insight into cellular potency and may provide a foundation for improved models of differentiation potency with far-reaching implications for the discovery of novel stem cell or progenitor cell phenotypes.
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Quantifying Waddington's Epigenetic Landscape: a comparison of single-cell potency measures
2018Co-Authors: Jifan Shi, Andrew E. Teschendorff, Weiyan Chen, Luonan ChenAbstract:Over 60 years ago Waddington proposed an Epigenetic Landscape model of cellular differentiation, whereby cell-fate transitions are modelled as canalization events, with stable cell states occupying the basins or attractor states. A key ingredient of this Landscape is the energy potential, or height, which correlates with cell-potency. To date, very few explicit biophysical models for estimating single-cell potency have been proposed. Using 9 independent experiments, encompassing over 6,600 high-quality single-cell RNA-Seq profiles, we here demonstrate that single-cell potency can be approximated as the graph entropy of a Markov Chain process on a model signaling network. Our analysis highlights that other proposed single-cell potency measures are not robust, whilst also revealing that integration with orthogonal systems-level information improves potency estimates. Thus, this study provides a foundation for an improved systems-level understanding of single-cell potency, which may have profound implications for the discovery of novel stem-and progenitor cell phenotypes.
Daniel G. Tenen - One of the best experts on this subject based on the ideXlab platform.
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The hematopoietic master regulator RUNX1 reshapes the Epigenetic Landscape at the onset of hematopoiesis
Epigenetics & Chromatin, 2013Co-Authors: Monika Lichtinger, Nadine Obier, Richard Ingram, Rebecca Hannah, Maarten Hoogenkamp, Vijayabaskar, Mengchu Wu, Salam A. Assi, Daniel G. Tenen, David R. WestheadAbstract:Hematopoiesis in the embryo originates from mesodermal cells and proceeds via a common precursor (hemangioblast) of endothelial cells and blood cells. Hemangioblasts give rise to specialised endothelial cells (hemogenic endothelium) which subsequently undergo a transition into hematopoietic precursor cells. These cell fate decisions are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI-1, PU.1 and C/EBP family members. In our work we study how dynamic shifts in the transcriptional regulatory network during this developmental pathway are regulated and how transcription factors control the activation of hematopoietic genes. We are also investigating, how these factors interact with each other and with the chromatin Landscape. To this end, we measured the genome-wide dynamics of chromatin alterations during the different steps of formation of the hematopoietic system from mesodermal cells using ES cell differentiation as model. We show that the hematopoietic program is already primed in the hemogenic endothelium as indicated by the binding of SCL/TAL1, FLI-1, C/EBPβ and enhancer-bound RNA-Polymerase II as well as the appearance of DNAsel hypersensitive sites. RUNX1 is absolutely required for the transition from hemogenic endothelium cells into hematopoietic progenitors. To obtain mechanistic information how this factor drives this process, we examined the assembly of hematopoietic transcription factors on their targets before and after this transition. Using an inducible system, we show that after induction RUNX1 binds to primed, but also novel elements and increases their histone acetylation. Moreover, RUNX1 initiates rapid global alterations in the binding patterns of SCL/TAL1 and FLI1, involving both the extinction of binding sites as well as the establishment of new sites. A significant fraction of new elements bind SCL/TAL1 and FLI1 in close proximity to RUNX1 in a pattern that is specific for hematopoietic cells. RUNX1 has previously shown to be expendable in hematopoietic precursor cells once they have formed from the hemogenic endothelium. By precisely timed withdrawal studies we show that immediately after RUNX1 induction altered transcription factor complex assembly at many genes is still reversible, but not at all of them. Our experiments suggest a dynamic interplay between RUNX1 and other transcription factors that dictates the half-life of factor assemblies and their dependency on RUNX1 and give a fascinating insight into how a single master regulator shapes the Epigenetic Landscape.
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runx1 reshapes the Epigenetic Landscape at the onset of haematopoiesis
The EMBO Journal, 2012Co-Authors: Monika Lichtinger, Richard Ingram, Rebecca Hannah, Salam A. Assi, Dorothee Muller, Deborah Clarke, Michael Liealing, Laura Noailles, M S Vijayabaskar, Daniel G. TenenAbstract:Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a Runx1−/− embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies.
Joby Cole - One of the best experts on this subject based on the ideXlab platform.
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pneumolysin is responsible for differential gene expression and modifications in the Epigenetic Landscape of primary monocyte derived macrophages
Frontiers in Immunology, 2021Co-Authors: Joby Cole, Timothy J Mitchell, Adrienn Angyal, Richard D. Emes, Mark J. Dickman, David H DockrellAbstract:Epigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of Epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the Epigenetic Landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF-α production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that Epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci.
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Pneumolysin is responsible for differential gene expression and modifications in the Epigenetic Landscape of primary monocyte derived macrophages.
2020Co-Authors: Joby Cole, Timothy J Mitchell, Adrienn Angyal, Richard D. Emes, Mark J. Dickman, David H DockrellAbstract:Abstract Epigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of Epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the Epigenetic Landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that Epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci. Author summary Pneumolysin is a toxin that contributes to how Streptococcus pneumoniae, the leading cause of pneumonia, causes disease. In this study, the toxin alters gene expression in immune cells called macrophages, one of the first lines of defence against bacteria at sites of infection. Modulation involved multiple immune responses, including generation of chemical signals coordinating responses in immune cells termed cytokines. In addition, changes were observed in histone proteins that are involved in controlling gene expression in the cell. Pneumolysin reduced early production of the cytokine TNF-α and a medicine vorinostat that modifies these ‘Epigenetic’ histone modifications had a similar affect, suggesting Epigenetic mechanisms contribute to the ability of pneumolysin to reduce immune responses.
Monika Lichtinger - One of the best experts on this subject based on the ideXlab platform.
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The hematopoietic master regulator RUNX1 reshapes the Epigenetic Landscape at the onset of hematopoiesis
Epigenetics & Chromatin, 2013Co-Authors: Monika Lichtinger, Nadine Obier, Richard Ingram, Rebecca Hannah, Maarten Hoogenkamp, Vijayabaskar, Mengchu Wu, Salam A. Assi, Daniel G. Tenen, David R. WestheadAbstract:Hematopoiesis in the embryo originates from mesodermal cells and proceeds via a common precursor (hemangioblast) of endothelial cells and blood cells. Hemangioblasts give rise to specialised endothelial cells (hemogenic endothelium) which subsequently undergo a transition into hematopoietic precursor cells. These cell fate decisions are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI-1, PU.1 and C/EBP family members. In our work we study how dynamic shifts in the transcriptional regulatory network during this developmental pathway are regulated and how transcription factors control the activation of hematopoietic genes. We are also investigating, how these factors interact with each other and with the chromatin Landscape. To this end, we measured the genome-wide dynamics of chromatin alterations during the different steps of formation of the hematopoietic system from mesodermal cells using ES cell differentiation as model. We show that the hematopoietic program is already primed in the hemogenic endothelium as indicated by the binding of SCL/TAL1, FLI-1, C/EBPβ and enhancer-bound RNA-Polymerase II as well as the appearance of DNAsel hypersensitive sites. RUNX1 is absolutely required for the transition from hemogenic endothelium cells into hematopoietic progenitors. To obtain mechanistic information how this factor drives this process, we examined the assembly of hematopoietic transcription factors on their targets before and after this transition. Using an inducible system, we show that after induction RUNX1 binds to primed, but also novel elements and increases their histone acetylation. Moreover, RUNX1 initiates rapid global alterations in the binding patterns of SCL/TAL1 and FLI1, involving both the extinction of binding sites as well as the establishment of new sites. A significant fraction of new elements bind SCL/TAL1 and FLI1 in close proximity to RUNX1 in a pattern that is specific for hematopoietic cells. RUNX1 has previously shown to be expendable in hematopoietic precursor cells once they have formed from the hemogenic endothelium. By precisely timed withdrawal studies we show that immediately after RUNX1 induction altered transcription factor complex assembly at many genes is still reversible, but not at all of them. Our experiments suggest a dynamic interplay between RUNX1 and other transcription factors that dictates the half-life of factor assemblies and their dependency on RUNX1 and give a fascinating insight into how a single master regulator shapes the Epigenetic Landscape.
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runx1 reshapes the Epigenetic Landscape at the onset of haematopoiesis
The EMBO Journal, 2012Co-Authors: Monika Lichtinger, Richard Ingram, Rebecca Hannah, Salam A. Assi, Dorothee Muller, Deborah Clarke, Michael Liealing, Laura Noailles, M S Vijayabaskar, Daniel G. TenenAbstract:Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a Runx1−/− embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies.