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2. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion

Author

Gangoso, Ester, Southgate, Benjamin, Bradley, Leanne, Rus, Stefanie, Galvez-Cancino, Felipe, McGivern, Niamh, Güç, Esra, Kapourani, Chantriolnt-Andreas, Byron, Adam, Ferguson, Kirsty M., Alfazema, Neza, Morrison, Gillian, Grant, Vivien, Blin, Carla, Sou, IengFong, Marques-Torrejon, Maria Angeles, Conde, Lucia, Parrinello, Simona, Herrero, Javier, Beck, Stephan, Brandner, Sebastian, Brennan, Paul M., Bertone, Paul, Pollard, Jeffrey W., Quezada, Sergio A., Sproul, Duncan, Frame, Margaret C., Serrels, Alan, and Pollard, Steven M.

Published
2021
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5. Distinct Molecular Trajectories Converge to Induce Naive Pluripotency

Author

Stuart, Hannah T., Stirparo, Giuliano G., Lohoff, Tim, Bates, Lawrence E., Kinoshita, Masaki, Lim, Chee Y., Sousa, Elsa J., Maskalenka, Katsiaryna, Radzisheuskaya, Aliaksandra, Malcolm, Andrew A., Alves, Mariana R.P., Lloyd, Rebecca L., Nestorowa, Sonia, Humphreys, Peter, Mansfield, William, Reik, Wolf, Bertone, Paul, Nichols, Jennifer, Göttgens, Berthold, and Silva, José C.R.

Published
2019
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6. DDEL-04. MODULATION OF THE BLOOD-TUMOR BARRIER FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA

Author

Jimenez-Macias, Jorge-Luis, primary, Xu, Zheyun, additional, Anthony, Doug, additional, Brodsky, Alex, additional, Tollefson, George, additional, Hawkins, William, additional, Schmidt, Andrea, additional, Sun, Michael, additional, Hong, Jason, additional, Forrest, Megan, additional, Nowicki, Michal, additional, Bertone, Paul, additional, and Lawler, Sean, additional

Published
2023
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9. Assessment of transcript reconstruction methods for RNA-seq.

Author

Steijger, Tamara, Abril, Josep F, Engström, Pär G, Kokocinski, Felix, RGASP Consortium, Hubbard, Tim J, Guigó, Roderic, Harrow, Jennifer, and Bertone, Paul

Subjects
RGASP Consortium, Animals, Humans, Drosophila melanogaster, Caenorhabditis elegans, RNA, Messenger, RNA Splice Sites, Gene Expression Profiling, Sequence Analysis, RNA, Computational Biology, RNA Splicing, Genome, Introns, Exons, Algorithms, Software, Genetics, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Technology, Medical and Health Sciences
Abstract

We evaluated 25 protocol variants of 14 independent computational methods for exon identification, transcript reconstruction and expression-level quantification from RNA-seq data. Our results show that most algorithms are able to identify discrete transcript components with high success rates but that assembly of complete isoform structures poses a major challenge even when all constituent elements are identified. Expression-level estimates also varied widely across methods, even when based on similar transcript models. Consequently, the complexity of higher eukaryotic genomes imposes severe limitations on transcript recall and splice product discrimination that are likely to remain limiting factors for the analysis of current-generation RNA-seq data.

Published
2013

12. Global Analysis of Protein Activities Using Proteome Chips

Author

Zhu, Heng, Bilgin, Metin, Bangham, Rhonda, Hall, David, Casamayor, Antonio, Bertone, Paul, Lan, Ning, Jansen, Ronald, Bidlingmaier, Scott, Houfek, Thomas, Mitchell, Tom, Miller, Perry, Dean, Ralph A., Gerstein, Mark, and Snyder, Michael

Published
2001

13. Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause

Author

Scognamiglio, Roberta, Cabezas-Wallscheid, Nina, Thier, Marc Christian, Altamura, Sandro, Reyes, Alejandro, Prendergast, Áine M., Baumgärtner, Daniel, Carnevalli, Larissa S., Atzberger, Ann, Haas, Simon, von Paleske, Lisa, Boroviak, Thorsten, Wörsdörfer, Philipp, Essers, Marieke A.G., Kloz, Ulrich, Eisenman, Robert N., Edenhofer, Frank, Bertone, Paul, Huber, Wolfgang, van der Hoeven, Franciscus, Smith, Austin, and Trumpp, Andreas

Published
2016
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15. Proximity proteomics reveals role of Abelson interactor 1 in the regulation of TAK1/RIPK1 signaling.

Author

Petersen, Max, Chorzalska, Anna, Pardo, Makayla, Rodriguez, Anaelena, Morgan, John, Ahsan, Nagib, Zhao, Ting C., Liang, Olin, Kotula, Leszek, Bertone, Paul, Gruppuso, Philip A., and Dubielecka, Patrycja M.

Abstract

Dysregulation of the adaptor protein Abelson interactor 1 (ABI1) is linked to malignant transformation. To interrogate the role of ABI1 in cancer development, we mapped the ABI1 interactome using proximity‐dependent labeling (PDL) with biotin followed by mass spectrometry. Using a novel PDL data filtering strategy, considering both peptide spectral matches and peak areas of detected peptides, we identified 212 ABI1 proximal interactors. These included WAVE2 complex components such as CYFIP1, NCKAP1, or WASF1, confirming the known role of ABI1 in the regulation of actin‐polymerization‐dependent processes. We also identified proteins associated with the TAK1‐IKK pathway, including TAK1, TAB2, and RIPK1, denoting a newly identified function of ABI1 in TAK1‐NF‐κB inflammatory signaling. Functional assays using TNFα‐stimulated, ABI1‐overexpressing or ABI1‐deficient cells showed effects on the TAK1‐NF‐kB pathway‐dependent signaling to RIPK1, with ABI1‐knockout cells being less susceptible to TNFα‐induced, RIPK1‐mediated, TAK1‐dependent apoptosis. In sum, our PDL‐based strategy enabled mapping of the ABI1 proximal interactome, thus revealing a previously unknown role of this adaptor protein in TAK1/RIPK1‐based regulation of cell death and survival. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Transcriptional diversity during lineage commitment of human blood progenitors

Author

Chen, Lu, Kostadima, Myrto, Martens, Joost H. A., Canu, Giovanni, Garcia, Sara P., Turro, Ernest, Downes, Kate, Macaulay, Iain C., Bielczyk-Maczynska, Ewa, Coe, Sophia, Farrow, Samantha, Poudel, Pawan, Burden, Frances, Jansen, Sjoert B. G., Astle, William J., Attwood, Antony, Bariana, Tadbir, de Bono, Bernard, Breschi, Alessandra, Chambers, John C., Consortium, BRIDGE, Choudry, Fizzah A., Clarke, Laura, Coupland, Paul, van der Ent, Martijn, Erber, Wendy N., Jansen, Joop H., Favier, Rémi, Fenech, Matthew E., Foad, Nicola, Freson, Kathleen, van Geet, Chris, Gomez, Keith, Guigo, Roderic, Hampshire, Daniel, Kelly, Anne M., Kerstens, Hindrik H. D., Kooner, Jaspal S., Laffan, Michael, Lentaigne, Claire, Labalette, Charlotte, Martin, Tiphaine, Meacham, Stuart, Mumford, Andrew, Nürnberg, Sylvia, Palumbo, Emilio, van der Reijden, Bert A., Richardson, David, Sammut, Stephen J., Slodkowicz, Greg, Tamuri, Asif U., Vasquez, Louella, Voss, Katrin, Watt, Stephen, Westbury, Sarah, Flicek, Paul, Loos, Remco, Goldman, Nick, Bertone, Paul, Read, Randy J., Richardson, Sylvia, Cvejic, Ana, Soranzo, Nicole, Ouwehand, Willem H., Stunnenberg, Hendrik G., Frontini, Mattia, and Rendon, Augusto

Published
2014

24. Citrullination regulates pluripotency and histone H1 binding to chromatin

Author

Christophorou, Maria A., Castelo-Branco, Goncalo, Halley-Stott, Richard P., Oliveira, Clara Slade, Loos, Remco, Radzisheuskaya, Aliaksandra, Mowen, Kerri A., Bertone, Paul, Silva, Jose C.R., Zernicka-Goetz, Magdalena, Nielsen, Michael L., Gurdon, John B., and Kouzarides, Tony

Subjects
Chromatin -- Physiological aspects -- Research, Blood clot -- Research -- Risk factors -- Complications and side effects -- Patient outcomes -- Genetic aspects, Stem cells -- Physiological aspects -- Research, Thrombosis -- Research -- Risk factors -- Complications and side effects -- Patient outcomes -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline (1). This modification leads to the loss of a positive charge and reduction in hydrogen-bonding ability. It is carried out by a small family oftissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) (2) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis (2,3). Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response (4-8). PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal (9), was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection (10). Here we show that the expression and enzymatic activity of Padi (4) are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. Padi (4) is part of the pluripotency transcriptional network, binding to regulatory elements of key stem-cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin (11), as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction., Pluripotent cells have the capacity to self-renew and differentiate into all somatic and germ-cell lineages and, hence, possess therapeutic potential for a multitude of medical conditions. Their generation by reprogramming [...]

Published
2014

25. Towards practical, high-capacity, low-maintenance information storage in synthesized DNA

Author

Goldman, Nick, Bertone, Paul, Chen, Siyuan, Dessimoz, Christophe, LeProust, Emily M., Sipos, Botond, and Birney, Ewan

Subjects
Computational biology -- Research, DNA -- Physiological aspects, Information storage and retrieval -- Management, Company business management, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Digital production, transmission and storage have revolutionized how we access and use information but have also made archiving an increasingly complex task that requires active, continuing maintenance of digital media. [...]

Published
2013

31. IMMUNOGENETICS: Transcriptional diversity during lineage commitment of human blood progenitors

Author

Chen, Lu, Kostadima, Myrto, Martens, Joost H. A., Canu, Giovanni, Garcia, Sara P., Turro, Ernest, Downes, Kate, Macaulay, Iain C., Bielczyk-Maczynska, Ewa, Coe, Sophia, Farrow, Samantha, Poudel, Pawan, Burden, Frances, Jansen, Sjoert B. G., Astle, William J., Attwood, Antony, Bariana, Tadbir, de Bono, Bernard, Breschi, Alessandra, Chambers, John C., Consortium, BRIDGE, Choudry, Fizzah A., Clarke, Laura, Coupland, Paul, van der Ent, Martijn, Erber, Wendy N., Jansen, Joop H., Favier, Rémi, Fenech, Matthew E., Foad, Nicola, Freson, Kathleen, van Geet, Chris, Gomez, Keith, Guigo, Roderic, Hampshire, Daniel, Kelly, Anne M., Kerstens, Hindrik H. D., Kooner, Jaspal S., Laffan, Michael, Lentaigne, Claire, Labalette, Charlotte, Martin, Tiphaine, Meacham, Stuart, Mumford, Andrew, Nürnberg, Sylvia, Palumbo, Emilio, van der Reijden, Bert A., Richardson, David, Sammut, Stephen J., Slodkowicz, Greg, Tamuri, Asif U., Vasquez, Louella, Voss, Katrin, Watt, Stephen, Westbury, Sarah, Flicek, Paul, Loos, Remco, Goldman, Nick, Bertone, Paul, Read, Randy J., Richardson, Sylvia, Cvejic, Ana, Soranzo, Nicole, Ouwehand, Willem H., Stunnenberg, Hendrik G., Frontini, Mattia, and Rendon, Augusto

Published
2014
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32. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification

Author

Boroviak, Thorsten, Loos, Remco, Bertone, Paul, Smith, Austin, Nichols, Jennifer, Bertone, Paul [0000-0001-5059-4829], Smith, Austin [0000-0002-3029-4682], Nichols, Jennifer [0000-0002-8650-1388], and Apollo - University of Cambridge Repository

Subjects
Pluripotent Stem Cells, Mice, 129 Strain, Gestational Age, Cell Line, Embryo Culture Techniques, Mice, Animals, Cell Lineage, Embryo Implantation, Extracellular Signal-Regulated MAP Kinases, reproductive and urinary physiology, Embryonic Stem Cells, Cell Proliferation, urogenital system, Gene Expression Profiling, Gene Expression Regulation, Developmental, Cell Differentiation, Clone Cells, Mice, Inbred C57BL, Phenotype, Blastocyst Inner Cell Mass, embryonic structures, Mice, Inbred CBA, Laminin, biological phenomena, cell phenomena, and immunity, Biomarkers, Germ Layers, Transcription Factors
Abstract

The precise relationship of embryonic stem cells (ESCs) to cells in the mouse embryo remains controversial. We present transcriptional and functional data to identify the embryonic counterpart of ESCs. Marker profiling shows that ESCs are distinct from early inner cell mass (ICM) and closely resemble pre-implantation epiblast. A characteristic feature of mouse ESCs is propagation without ERK signalling. Single-cell culture reveals that cell-autonomous capacity to thrive when the ERK pathway is inhibited arises late during blastocyst development and is lost after implantation. The frequency of deriving clonal ESC lines suggests that all E4.5 epiblast cells can become ESCs. We further show that ICM cells from early blastocysts can progress to ERK independence if provided with a specific laminin substrate. These findings suggest that formation of the epiblast coincides with competence for ERK-independent self-renewal in vitro and consequent propagation as ESC lines.

Published
2019
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36. Target hub proteins serve as master regulators of development in yeast

Author

Borneman, Anthony R., Snyder, Michael, Leigh-Bell, Justine A., Bertone, Paul, Haiyuan Yu, and Gerstein, Mark

Subjects
Yeast fungi -- Genetic aspects, Brewer's yeast -- Genetic aspects, Eukaryotes -- Research, Biological sciences
Abstract

An investigation of the transcriptional circuitry controlling pseudohyphal development in Saccharomyces cerevisiae to understand the organization of the transcriptional networks that govern cell differentiation is presented. Target hubs can serve as master regulators whose activity is sufficient for the induction of complex developmental responses and therefore represent important regulatory nodes in biological networks.

Published
2006

37. Analysis of Genomic Tiling Microarrays for Transcript Mapping and the Identification of Transcription Factor Binding Sites

Author

Rozowsky, Joel, Bertone, Paul, Royce, Thomas, Weissman, Sherman, Snyder, Michael, Gerstein, Mark, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Dough, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Istrail, Sorin, editor, Pevzner, Pavel, editor, Waterman, Michael, editor, Setubal, João Carlos, editor, and Verjovski-Almeida, Sergio, editor

Published
2005
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38. Global changes in STAT target selection and transcription regulation upon interferon treatments

Author

Hartman, Stephen E., Bertone, Paul, Nath, Anjali K., Royce, Thomas E., Weissman, Sherman, and Snyder, Michael

Subjects
Transducers -- Research, Human chromosomes -- Research, DNA-ligand interactions -- Research, Genetic research, Biological sciences
Abstract

The regions of human chromosome 22 bound by Single Transducers and Activators of Transcription (STAT)1 and STAT2 in interferon-treated cells are identified using chromatin immunoprecipitation and DNA microarray analysis. Results demonstrate that the DNA-binding behavior of STAT1 homodimers is not conserved between the different interferon treatment conditions.

Published
2005

40. Distribution of NF-[kappa]B-binding sites across human chromosome 22

Author

Martone, Rebecca, Euskirchen, Ghia, Bertone, Paul, Hartman, Stephen, Royce, Thomas E., Luscombe, Nicholas M., Rinn, John L., Nelson, F. Kenneth, Miller, Perry, Gerstein, Mark, Weissman, Sherman, and Snyder, Michael

Subjects
Cells -- Research, Science and technology
Abstract

We have mapped the chromosomal binding site distribution of a transcription factor in human cells. The NF-[kappa]B family of transcription factors plays an essential role in regulating the induction of genes involved in several physiological processes, including apoptosis, immunity, and inflammation. The binding sites of the NF-[kappa]B family member p65 were determined by using chromatin immunoprecipitation and a genomic microarray of human chromosome 22 DNA. Sites of binding were observed along the entire chromosome in both coding and noncoding regions, with an enrichment at the 5' end of genes. Strikingly, a significant proportion of binding was seen in intronic regions, demonstrating that transcription factor binding is not restricted to promoter regions. NF-[kappa]B binding was also found at genes whose expression was regulated by tumor necrosis factor [alpha], a known inducer of NF-[kappa]B-dependent gene expression, as well as adjacent to genes whose expression is not affected by tumor necrosis factor [alpha]. Many of these latter genes are either known to be activated by NF-[kappa]B under other conditions or are consistent with NF-[kappa]B's role in the immune and apoptotic responses. Our results suggest that binding is not restricted to promoter regions and that NF-KB binding occurs at a significant number of genes whose expression is not altered, thereby suggesting that binding alone is not sufficient for gene activation.

Published
2003

42. Naive Pluripotent Stem Cells Derived Directly from Isolated Cells of the Human Inner Cell Mass

Author

Guo, Ge, von Meyenn, Ferdinand, Santos, Fatima, Chen, Yaoyao, Reik, Wolf, Bertone, Paul, Smith, Austin, Nichols, Jennifer, Reik, Wolf [0000-0003-0216-9881], Bertone, Paul [0000-0001-5059-4829], Smith, Austin [0000-0002-3029-4682], Nichols, Jennifer [0000-0002-8650-1388], and Apollo - University of Cambridge Repository

Subjects
Pluripotent Stem Cells, lcsh:R5-920, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Human Embryonic Stem Cells, Fluorescent Antibody Technique, Cell Differentiation, DNA Methylation, Cell Line, Mice, Blastocyst, lcsh:Biology (General), Report, Animals, Humans, Cell Lineage, Myocytes, Cardiac, lcsh:Medicine (General), lcsh:QH301-705.5, Cells, Cultured, Germ Layers, Cell Proliferation, Signal Transduction
Abstract

Summary Conventional generation of stem cells from human blastocysts produces a developmentally advanced, or primed, stage of pluripotency. In vitro resetting to a more naive phenotype has been reported. However, whether the reset culture conditions of selective kinase inhibition can enable capture of naive epiblast cells directly from the embryo has not been determined. Here, we show that in these specific conditions individual inner cell mass cells grow into colonies that may then be expanded over multiple passages while retaining a diploid karyotype and naive properties. The cells express hallmark naive pluripotency factors and additionally display features of mitochondrial respiration, global gene expression, and genome-wide hypomethylation distinct from primed cells. They transition through primed pluripotency into somatic lineage differentiation. Collectively these attributes suggest classification as human naive embryonic stem cells. Human counterparts of canonical mouse embryonic stem cells would argue for conservation in the phased progression of pluripotency in mammals., Graphical Abstract, Highlights • Karyotypically normal pluripotent stem cells derived from single human ICM cells • Expanded lines retain anticipated molecular features of naive embryonic stem cells • Consistency between ICM-derived and in vitro reset naive human pluripotent stem cells • Presence of KLF17 protein in human ICM and naive stem cells, In this paper, Nichols, Smith, and colleagues show that stem cells can be derived from human embryos by dissociation of the inner cell mass into single cells and culture in conditions that suppress further differentiation. Molecular profiling indicates a more naive status than previously observed for human embryonic stem cell lines.

Published
2016

43. Complex transcriptional circuitry at the G1/S transition in Saccharomyces cerevisiae

Author

Horak, Christine E., Luscombe, Nicholas M., Qian, Jiang, Piccirrillo, Stacy, Gerstein, Mark, Snyder, Michael, and Bertone, Paul

Subjects
Genetic research -- Analysis, Brewer's yeast -- Genetic aspects, Genetic transcription -- Physiological aspects, Cell cycle -- Genetic aspects, Genetic regulation -- Physiological aspects, Biological sciences
Abstract

Research has been conducted on cell cycle regulation in Saccharomyces cerevisiae. The study of the transcription factors' gene targets implicated in G1/S control suggests that a regulatory cascade may control the events which surround cell cycle START.

Published
2002

45. Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development

Author

Boroviak, Thorsten, Stirparo, Giuliano G., Dietmann, Sabine, Hernando-Herraez, Irene, Mohammed, Hisham, Reik, Wolf, Smith, Austin, Sasaki, Erika, Nichols, Jennifer, Bertone, Paul, Boroviak, Thorsten [0000-0001-8703-8949], Reik, Wolf [0000-0003-0216-9881], Smith, Austin [0000-0002-3029-4682], Nichols, Jennifer [0000-0002-8650-1388], Bertone, Paul [0000-0001-5059-4829], and Apollo - University of Cambridge Repository

Subjects
Pluripotency, animal structures, Transcription, Genetic, Human Development, Embryonic Development, Epigenesis, Genetic, Mice, Animals, Humans, Gene Regulatory Networks, RNA, Messenger, Conserved Sequence, Otx Transcription Factors, Primate, Gene Expression Profiling, Endoderm, Gene Expression Regulation, Developmental, Callithrix, Embryo, Mammalian, Blastocyst, Embryo, embryonic structures, Inner cell mass, Single-Cell Analysis, Transcriptome, Ribosomes, Germ Layers, Human
Abstract

The mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single cell RNA-seq. Zygotic genome activation correlates with the presence of polycomb repressive complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species, stage and lineage specific. The pluripotency network in the primate epiblast lacks certain regulators that are operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and non-human primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development, and underscores the molecular adaptability of early mammalian embryogenesis., Highlighted Article: Analysis of stage-matched, single-cell gene expression data from three mammalian species reveals conserved and primate-specific regulation of early embryogenesis and lineage specification.

Published
2018

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