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  1. Article ; Online: T cell immunity is key to the pandemic endgame

    Megan Schwarz / Slim Mzoughi / Daniel Lozano-Ojalvo / Anthony T. Tan / Antonio Bertoletti / Ernesto Guccione

    Current Research in Immunology, Vol 3, Iss , Pp 215-

    How to measure and monitor it

    2022  Volume 221

    Abstract: As vaccine deployment improves the healthcare emergency status caused by the SARS-CoV-2 pandemic, we need reliable tools to evaluate the duration of protective immunity at a global scale. Seminal studies have demonstrated that while neutralizing ... ...

    Abstract As vaccine deployment improves the healthcare emergency status caused by the SARS-CoV-2 pandemic, we need reliable tools to evaluate the duration of protective immunity at a global scale. Seminal studies have demonstrated that while neutralizing antibodies can protect us from viral infection, T cell-mediated cellular immunity provides long-term protection from severe COVID-19, even in the case of emerging new variants of concern (VOC). Indeed, the emergence of VOCs, able to substantially escape antibodies generated by current vaccines, has made the analysis of correlates of humoral protection against infection obsolete. The focus should now shift towards immunological correlates of protection from disease based on quantification of cellular immunity.Despite this evidence, an assessment of T cell responses is still overlooked. This is largely due to technical challenges and lack of validated diagnostic tests. Here, we review the current state of the art of available tests to distinguish between SARS-CoV-2 antigen-specific Tcells and non-antigen specific T-cells. These assays range from the analysis of the T cell-receptor (TCR) diversity (i.e. Immunoseq and MHC tetramer staining) to the detection of functional T cell activation (i.e. ICS, AIM, Elispot, ELLA, dqTACT, etc.) either from purified Peripheral Blood Mononuclear Cells (PBMCs) or whole blood.We discuss advantages and disadvantages of each assay, proposing their ideal use for different scopes. Finally, we argue how it is paramount to deploy cheap, standardized, and scalable assays to measure T cell functionality to fill this critical diagnostic gap and manage these next years of the pandemic.
    Keywords T-cells ; SARS-CoV-2 ; Cellular immunity ; qPCR ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: An interplay between BRD4 and G9a regulates skeletal myogenesis

    Naidi Yang / Dipanwita Das / Shilpa Rani Shankar / Pierre-Alexis Goy / Ernesto Guccione / Reshma Taneja

    Frontiers in Cell and Developmental Biology, Vol

    2022  Volume 10

    Abstract: Histone acetylation and methylation are epigenetic modifications that are dynamically regulated by chromatin modifiers to precisely regulate gene expression. However, the interplay by which histone modifications are synchronized to coordinate cellular ... ...

    Abstract Histone acetylation and methylation are epigenetic modifications that are dynamically regulated by chromatin modifiers to precisely regulate gene expression. However, the interplay by which histone modifications are synchronized to coordinate cellular differentiation is not fully understood. In this study, we demonstrate a relationship between BRD4, a reader of acetylation marks, and G9a, a writer of methylation marks in the regulation of myogenic differentiation. Using loss- and gain-of-function studies, as well as a pharmacological inhibition of its activity, we examined the mechanism by which BRD4 regulates myogenesis. Transcriptomic analysis using RNA sequencing revealed that a number of myogenic differentiation genes are downregulated in Brd4-depleted cells. Interestingly, some of these genes were upregulated upon G9a knockdown, indicating that BRD4 and G9a play opposing roles in the control of myogenic gene expression. Remarkably, the differentiation defect caused by Brd4 knockdown was rescued by inhibition of G9a methyltransferase activity. These findings demonstrate that the absence of BRD4 results in the upregulation of G9a activity and consequently impaired myogenic differentiation. Collectively, our study identifies an interdependence between BRD4 and G9a for the precise control of transcriptional outputs to regulate myogenesis.
    Keywords differentiation ; writer ; reader ; methylation ; acetylation ; muscle ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2022-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Npac Is A Co-factor of Histone H3K36me3 and Regulates Transcriptional Elongation in Mouse Embryonic Stem Cells

    Sue Yu / Jia Li / Guanxu Ji / Zhen Long Ng / Jiamin Siew / Wan Ning Lo / Ying Ye / Yuan Yuan Chew / Yun Chau Long / Wensheng Zhang / Ernesto Guccione / Yuin Han Loh / Zhi-Hong Jiang / Henry Yang / Qiang Wu

    Genomics, Proteomics & Bioinformatics, Vol 20, Iss 1, Pp 110-

    2022  Volume 128

    Abstract: Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a “reader” of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain ... ...

    Abstract Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a “reader” of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain mouse ESC (mESC) pluripotency since knockdown of Npac causes mESC differentiation. Depletion of Npac in mouse embryonic fibroblasts (MEFs) inhibits reprogramming efficiency. Furthermore, our chromatin immunoprecipitation followed by sequencing (ChIP-seq) results of Npac reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs. Interestingly, we find that Npac interacts with positive transcription elongation factor b (p-TEFb), Ser2-phosphorylated RNA Pol II (RNA Pol II Ser2P), and Ser5-phosphorylated RNA Pol II (RNA Pol II Ser5P). Furthermore, depletion of Npac disrupts transcriptional elongation of the pluripotency genes Nanog and Rif1. Taken together, we propose that Npac is essential for the transcriptional elongation of pluripotency genes by recruiting p-TEFb and interacting with RNA Pol II Ser2P and Ser5P.
    Keywords Npac ; Pluripotency ; Reprogramming ; Histone H3K36me3 ; Transcriptional elongation ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Isoform-resolved transcriptome of the human preimplantation embryo

    Denis Torre / Nancy J. Francoeur / Yael Kalma / Ilana Gross Carmel / Betsaida S. Melo / Gintaras Deikus / Kimaada Allette / Ron Flohr / Maya Fridrikh / Konstantinos Vlachos / Kent Madrid / Hardik Shah / Ying-Chih Wang / Shwetha H. Sridhar / Melissa L. Smith / Efrat Eliyahu / Foad Azem / Hadar Amir / Yoav Mayshar /
    Ivan Marazzi / Ernesto Guccione / Eric Schadt / Dalit Ben-Yosef / Robert Sebra

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 23

    Abstract: Abstract Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an ... ...

    Abstract Abstract Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.
    Keywords Science ; Q
    Subject code 572
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing

    Sayan Chakraborty / Divyaleka Sampath / Melissa Ong Yu Lin / Matthew Bilton / Cheng-Kuang Huang / Mui Hoon Nai / Kizito Njah / Pierre-Alexis Goy / Cheng-Chun Wang / Ernesto Guccione / Chwee-Teck Lim / Wanjin Hong

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 18

    Abstract: Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing ... ...

    Abstract Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing efficient skin wound healing.
    Keywords Science ; Q
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma

    Maxine S. Y. Lam / Jose Antonio Reales-Calderon / Jin Rong Ow / Joey J. Y. Aw / Damien Tan / Ragavi Vijayakumar / Erica Ceccarello / Tommaso Tabaglio / Yan Ting Lim / Wang Loo Chien / Fritz Lai / Anthony Tan Tanoto / Qingfeng Chen / Radoslaw M. Sobota / Giulia Adriani / Antonio Bertoletti / Ernesto Guccione / Andrea Pavesi

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 18

    Abstract: Engineered T cells are used for tumour immunotherapy but can have side effects and need multiple treatment rounds. Here during expansion of T cells from patients, the authors use an inhibitor of the epigenetic regulator G9a/GLP and show that this ... ...

    Abstract Engineered T cells are used for tumour immunotherapy but can have side effects and need multiple treatment rounds. Here during expansion of T cells from patients, the authors use an inhibitor of the epigenetic regulator G9a/GLP and show that this increases T cell cytotoxic function and tumour reduction in vitro and in vivo respectively.
    Keywords Science ; Q
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Global translation during early development depends on the essential transcription factor PRDM10

    Brenda Y. Han / Michelle K. Y. Seah / Imogen R. Brooks / Delia H. P. Quek / Dominic R. Huxley / Chuan-Sheng Foo / Li Ting Lee / Heike Wollmann / Huili Guo / Daniel M. Messerschmidt / Ernesto Guccione

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: PRDM family members are transcriptional regulators involved in cell identity and fate determination. Here, the authors characterize PRDM10 and show that it functions to ensure global translation efficiency during early embryonic development. ...

    Abstract PRDM family members are transcriptional regulators involved in cell identity and fate determination. Here, the authors characterize PRDM10 and show that it functions to ensure global translation efficiency during early embryonic development.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma

    Ananya Pal / Jia Yu Leung / Gareth Chin Khye Ang / Vinay Kumar Rao / Luca Pignata / Huey Jin Lim / Maxime Hebrard / Kenneth TE Chang / Victor KM Lee / Ernesto Guccione / Reshma Taneja

    eLife, Vol

    2020  Volume 9

    Abstract: Wnt signaling is downregulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way toward novel therapeutic modalities. We demonstrate ... ...

    Abstract Wnt signaling is downregulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way toward novel therapeutic modalities. We demonstrate that EHMT2 suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of EHMT2 expression or activity in human ERMS cell lines reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in mouse xenograft models in vivo. Mechanistically, EHMT2 impacted Sp1 and p300 enrichment at the DKK1 promoter. The reduced tumor growth upon EHMT2 deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among 13 drugs targeting chromatin modifiers, EHMT2 inhibitors were highly effective in reducing ERMS cell viability. Our study demonstrates that ERMS cells are vulnerable to EHMT2 inhibitors and suggest that targeting the EHMT2-DKK1-β-catenin node holds promise for differentiation therapy.
    Keywords epigenetics ; methylation ; cancer ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Modeling Cerebrovascular Pathophysiology in Amyloid-β Metabolism using Neural-Crest-Derived Smooth Muscle Cells

    Christine Cheung / Yeek Teck Goh / Jingxian Zhang / Chenghan Wu / Ernesto Guccione

    Cell Reports, Vol 9, Iss 1, Pp 391-

    2014  Volume 401

    Abstract: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we ...

    Abstract There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
    Keywords Biology (General) ; QH301-705.5
    Subject code 571 ; 610
    Language English
    Publishing date 2014-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells

    Vin Yee Chung / Tuan Zea Tan / Jieru Ye / Rui-Lan Huang / Hung-Cheng Lai / Dennis Kappei / Heike Wollmann / Ernesto Guccione / Ruby Yun-Ju Huang

    Communications Biology, Vol 2, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Vin Yee Chung et al. identify differentially methylated CpG sites in the promoters of epithelial genes and GRHL2 binding sites in ovarian cancer cells during the epithelial–mesenchymal transition. They find that GRHL2 knockdown or overexpression affects ... ...

    Abstract Vin Yee Chung et al. identify differentially methylated CpG sites in the promoters of epithelial genes and GRHL2 binding sites in ovarian cancer cells during the epithelial–mesenchymal transition. They find that GRHL2 knockdown or overexpression affects methylation, suggesting a role for this transcription factor in epigenetic remodeling.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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