ALBERT

Description: Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242194/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242194/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saeed, Sadia -- Quintin, Jessica -- Kerstens, Hindrik H D -- Rao, Nagesha A -- Aghajanirefah, Ali -- Matarese, Filomena -- Cheng, Shih-Chin -- Ratter, Jacqueline -- Berentsen, Kim -- van der Ent, Martijn A -- Sharifi, Nilofar -- Janssen-Megens, Eva M -- Ter Huurne, Menno -- Mandoli, Amit -- van Schaik, Tom -- Ng, Aylwin -- Burden, Frances -- Downes, Kate -- Frontini, Mattia -- Kumar, Vinod -- Giamarellos-Bourboulis, Evangelos J -- Ouwehand, Willem H -- van der Meer, Jos W M -- Joosten, Leo A B -- Wijmenga, Cisca -- Martens, Joost H A -- Xavier, Ramnik J -- Logie, Colin -- Netea, Mihai G -- Stunnenberg, Hendrik G -- P30 DK043351/DK/NIDDK NIH HHS/ -- RG/09/012/28096/British Heart Foundation/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1251086. doi: 10.1126/science.1251086.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. ; Department of Haematology, University of Cambridge, Cambridge, UK. National Health Service, Blood and Transplant Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB0 2PT, UK. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. ; Fourth Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Street, 12462 Athens, Greece. ; Department of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. h.stunnenberg@ncmls.ru.nl mihai.netea@radboudumc.nl c.logie@ncmls.ru.nl. ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. h.stunnenberg@ncmls.ru.nl mihai.netea@radboudumc.nl c.logie@ncmls.ru.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258085" target="_blank"〉PubMed〈/a〉

Description: Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- BRIDGE Consortium -- Choudry, Fizzah A -- Clarke, Laura -- Coupland, Paul -- van der Ent, Martijn -- Erber, Wendy N -- Jansen, Joop H -- Favier, Remi -- 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 -- Nurnberg, 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 -- Rendon, Augusto -- 082961/Wellcome Trust/United Kingdom -- 082961/Z/07/Z/Wellcome Trust/United Kingdom -- 084183/Z/07/Z/Wellcome Trust/United Kingdom -- 095908/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- C45041/A14953/Cancer Research UK/United Kingdom -- FS/12/27/29405/British Heart Foundation/United Kingdom -- MC_UP_0801/1/Medical Research Council/United Kingdom -- MR/J011711/1/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- MR/K023489/1/Medical Research Council/United Kingdom -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RG/09/12/28096/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/Department of Health/United Kingdom -- WT091310/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1251033. doi: 10.1126/science.1251033.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Molecular Biology, Radboud University, 6525 GA Nijmegen, Netherlands. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK. The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; CHIME Institute, University College London, Archway Campus, London NW1 2DA, UK. Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand. ; Centre for Genomic Regulation and University Pompeu Fabra, 08002 Barcelona, Spain. ; Imperial College Healthcare NHS Trust, DuCane Road, London W12 0HS, UK. Ealing Hospital NHS Trust, Southall, Middlesex UB1 3HW, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia. ; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Assistance Publique-Hopitaux de Paris, INSERM U1009, 94805 Villejuif, France. ; Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK. ; Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. ; The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge B2 0QQ, UK. ; Department of Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Twin Research & Genetic Epidemiology, Genetics and Molecular Medicine Division, St Thomas' Hospital, King's College, London SE1 7EH, UK. ; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK. ; Department of Oncology, Addenbrooke's Cambridge University Hospital NHS Trust, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. Cancer Research UK, Cambridge Institute, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. ; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. ; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ar506@cam.ac.uk mf471@cam.ac.uk. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ar506@cam.ac.uk mf471@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258084" target="_blank"〉PubMed〈/a〉

Description: Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1alpha (hypoxia-inducible factor-1alpha) pathway. Inhibition of Akt, mTOR, or HIF-1alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1alpha pathway represents the metabolic basis of trained immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226238/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226238/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Shih-Chin -- Quintin, Jessica -- Cramer, Robert A -- Shepardson, Kelly M -- Saeed, Sadia -- Kumar, Vinod -- Giamarellos-Bourboulis, Evangelos J -- Martens, Joost H A -- Rao, Nagesha Appukudige -- Aghajanirefah, Ali -- Manjeri, Ganesh R -- Li, Yang -- Ifrim, Daniela C -- Arts, Rob J W -- van der Veer, Brian M J W -- Deen, Peter M T -- Logie, Colin -- O'Neill, Luke A -- Willems, Peter -- van de Veerdonk, Frank L -- van der Meer, Jos W M -- Ng, Aylwin -- Joosten, Leo A B -- Wijmenga, Cisca -- Stunnenberg, Hendrik G -- Xavier, Ramnik J -- Netea, Mihai G -- 1P30GM106394-01/GM/NIGMS NIH HHS/ -- 5P30GM103415-03/GM/NIGMS NIH HHS/ -- DK097485/DK/NIDDK NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 GM103415/GM/NIGMS NIH HHS/ -- P30 GM106394/GM/NIGMS NIH HHS/ -- R01 AI081838/AI/NIAID NIH HHS/ -- R01 DK097485/DK/NIDDK NIH HHS/ -- R01AI81838/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1250684. doi: 10.1126/science.1250684.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. ; 4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece. ; Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. ; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. mihai.netea@radboudumc.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258083" target="_blank"〉PubMed〈/a〉