Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells
Identifieur interne : 000136 ( Pmc/Checkpoint ); précédent : 000135; suivant : 000137Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells
Auteurs : Wen Juan Tu [Australie] ; Kristine Hardy [Australie] ; Christopher R. Sutton [Australie] ; Robert Mccuaig [Australie] ; Jasmine Li [Australie] ; Jenny Dunn [Australie] ; Abel Tan [Australie] ; Vedran Brezar [France] ; Melanie Morris [Australie] ; Gareth Denyer [Australie] ; Sau Kuen Lee [Australie] ; Stephen J. Turner [Australie] ; Nabila Seddiki [France] ; Corey Smith [Australie] ; Rajiv Khanna [Australie] ; Sudha Rao [Australie]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Memory T cells exhibit transcriptional memory and “remember” their previous pathogenic encounter to increase transcription on re-infection. However, how this transcriptional priming response is regulated is unknown. Here we performed global FAIRE-seq profiling of chromatin accessibility in a human T cell transcriptional memory model. Primary activation induced persistent accessibility changes, and secondary activation induced secondary-specific opening of previously less accessible regions associated with enhanced expression of memory-responsive genes. Increased accessibility occurred largely in distal regulatory regions and was associated with increased histone acetylation and relative H3.3 deposition. The enhanced re-stimulation response was linked to the strength of initial PKC-induced signalling, and PKC-sensitive increases in accessibility upon initial stimulation showed higher accessibility on re-stimulation. While accessibility maintenance was associated with ETS-1, accessibility at re-stimulation-specific regions was linked to NFAT, especially in combination with ETS-1, EGR, GATA, NFκB, and NR4A. Furthermore,
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DOI: 10.1038/srep44825
PubMed: 28317936
PubMed Central: 5357947
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells</title><author><name sortKey="Tu, Wen Juan" sort="Tu, Wen Juan" uniqKey="Tu W" first="Wen Juan" last="Tu">Wen Juan Tu</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hardy, Kristine" sort="Hardy, Kristine" uniqKey="Hardy K" first="Kristine" last="Hardy">Kristine Hardy</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sutton, Christopher R" sort="Sutton, Christopher R" uniqKey="Sutton C" first="Christopher R." last="Sutton">Christopher R. Sutton</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mccuaig, Robert" sort="Mccuaig, Robert" uniqKey="Mccuaig R" first="Robert" last="Mccuaig">Robert Mccuaig</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jasmine" sort="Li, Jasmine" uniqKey="Li J" first="Jasmine" last="Li">Jasmine 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Stephen J" sort="Turner, Stephen J" uniqKey="Turner S" first="Stephen J." last="Turner">Stephen J. Turner</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Microbiology, Biomedical Discovery Institute, Monash University</institution>, Clayton, Victoria 3800,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne</institution>, Victoria 3010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Seddiki, Nabila" sort="Seddiki, Nabila" uniqKey="Seddiki N" first="Nabila" last="Seddiki">Nabila Seddiki</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute</institution>, Creteil 94010,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Smith, Corey" sort="Smith, Corey" uniqKey="Smith C" first="Corey" last="Smith">Corey Smith</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># 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id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sutton, Christopher R" sort="Sutton, Christopher R" uniqKey="Sutton C" first="Christopher R." last="Sutton">Christopher R. Sutton</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mccuaig, Robert" sort="Mccuaig, Robert" uniqKey="Mccuaig R" first="Robert" last="Mccuaig">Robert Mccuaig</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jasmine" sort="Li, Jasmine" uniqKey="Li J" first="Jasmine" last="Li">Jasmine Li</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Microbiology, Biomedical Discovery Institute, Monash University</institution>, Clayton, Victoria 3800,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne</institution>, Victoria 3010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dunn, Jenny" sort="Dunn, Jenny" uniqKey="Dunn J" first="Jenny" last="Dunn">Jenny Dunn</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Abel" sort="Tan, Abel" uniqKey="Tan A" first="Abel" last="Tan">Abel Tan</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brezar, Vedran" sort="Brezar, Vedran" uniqKey="Brezar V" first="Vedran" last="Brezar">Vedran Brezar</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute</institution>, Creteil 94010,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Morris, Melanie" sort="Morris, Melanie" uniqKey="Morris M" first="Melanie" last="Morris">Melanie Morris</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Denyer, Gareth" sort="Denyer, Gareth" uniqKey="Denyer G" first="Gareth" last="Denyer">Gareth Denyer</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>School of Molecular Bioscience, The University of Sydney</institution>, Sydney, NSW,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Sau Kuen" sort="Lee, Sau Kuen" uniqKey="Lee S" first="Sau Kuen" last="Lee">Sau Kuen Lee</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Turner, Stephen J" sort="Turner, Stephen J" uniqKey="Turner S" first="Stephen J." last="Turner">Stephen J. Turner</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Microbiology, Biomedical Discovery Institute, Monash University</institution>, Clayton, Victoria 3800,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne</institution>, Victoria 3010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Seddiki, Nabila" sort="Seddiki, Nabila" uniqKey="Seddiki N" first="Nabila" last="Seddiki">Nabila Seddiki</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute</institution>, Creteil 94010,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Smith, Corey" sort="Smith, Corey" uniqKey="Smith C" first="Corey" last="Smith">Corey Smith</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Khanna, Rajiv" sort="Khanna, Rajiv" uniqKey="Khanna R" first="Rajiv" last="Khanna">Rajiv Khanna</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rao, Sudha" sort="Rao, Sudha" uniqKey="Rao S" first="Sudha" last="Rao">Sudha Rao</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Memory T cells exhibit transcriptional memory and “remember” their previous pathogenic encounter to increase transcription on re-infection. However, how this transcriptional priming response is regulated is unknown. Here we performed global FAIRE-seq profiling of chromatin accessibility in a human T cell transcriptional memory model. Primary activation induced persistent accessibility changes, and secondary activation induced secondary-specific opening of previously less accessible regions associated with enhanced expression of memory-responsive genes. Increased accessibility occurred largely in distal regulatory regions and was associated with increased histone acetylation and relative H3.3 deposition. The enhanced re-stimulation response was linked to the strength of initial PKC-induced signalling, and PKC-sensitive increases in accessibility upon initial stimulation showed higher accessibility on re-stimulation. While accessibility maintenance was associated with ETS-1, accessibility at re-stimulation-specific regions was linked to NFAT, especially in combination with ETS-1, EGR, GATA, NFκB, and NR4A. Furthermore, <italic>NFATC1</italic> was directly regulated by ETS-1 at an enhancer region. In contrast to the factors that increased accessibility, signalling from bHLH and ZEB family members enhanced decreased accessibility upon re-stimulation. Interplay between distal regulatory elements, accessibility, and the combined action of sequence-specific transcription factors allows transcriptional memory-responsive genes to “remember” their initial environmental encounter.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weng, N P" uniqKey="Weng N">N. P. Weng</name></author><author><name sortKey="Araki, Y" uniqKey="Araki Y">Y. Araki</name></author><author><name sortKey="Subedi, K" uniqKey="Subedi K">K. Subedi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, K" uniqKey="Liu K">K. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28317936</article-id><article-id pub-id-type="pmc">5357947</article-id><article-id pub-id-type="pii">srep44825</article-id><article-id pub-id-type="doi">10.1038/srep44825</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tu</surname><given-names>Wen Juan</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>Kristine</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Sutton</surname><given-names>Christopher R.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>McCuaig</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jasmine</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dunn</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Abel</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brezar</surname><given-names>Vedran</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Morris</surname><given-names>Melanie</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Denyer</surname><given-names>Gareth</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Sau Kuen</given-names></name><xref ref-type="aff" rid="a6">6</xref><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Seddiki</surname><given-names>Nabila</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Corey</given-names></name><xref ref-type="aff" rid="a6">6</xref><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Khanna</surname><given-names>Rajiv</given-names></name><xref ref-type="aff" rid="a6">6</xref><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Sudha</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><aff id="a1"><label>1</label><institution>Faculty of Education, Science, Technology & Mathematics, University of Canberra</institution>, Canberra, Australian Capital Territory 2617,<country>Australia</country></aff><aff id="a2"><label>2</label><institution>Department of Microbiology, Biomedical Discovery Institute, Monash University</institution>, Clayton, Victoria 3800,<country>Australia</country></aff><aff id="a3"><label>3</label><institution>Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne</institution>, Victoria 3010,<country>Australia</country></aff><aff id="a4"><label>4</label><institution>INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute</institution>, Creteil 94010,<country>France</country></aff><aff id="a5"><label>5</label><institution>School of Molecular Bioscience, The University of Sydney</institution>, Sydney, NSW,<country>Australia</country></aff><aff id="a6"><label>6</label><institution>QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></aff><aff id="a7"><label>7</label><institution>Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute</institution>, Brisbane, Queensland,<country>Australia</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>sudha.rao@canberra.edu.au</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>20</day><month>03</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>44825</elocation-id><history><date date-type="received"><day>28</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>14</day><month>02</month><year>2017</year></date></history><permissions><copyright-statement>Copyright © 2017, The Author(s)</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Memory T cells exhibit transcriptional memory and “remember” their previous pathogenic encounter to increase transcription on re-infection. However, how this transcriptional priming response is regulated is unknown. Here we performed global FAIRE-seq profiling of chromatin accessibility in a human T cell transcriptional memory model. Primary activation induced persistent accessibility changes, and secondary activation induced secondary-specific opening of previously less accessible regions associated with enhanced expression of memory-responsive genes. Increased accessibility occurred largely in distal regulatory regions and was associated with increased histone acetylation and relative H3.3 deposition. The enhanced re-stimulation response was linked to the strength of initial PKC-induced signalling, and PKC-sensitive increases in accessibility upon initial stimulation showed higher accessibility on re-stimulation. While accessibility maintenance was associated with ETS-1, accessibility at re-stimulation-specific regions was linked to NFAT, especially in combination with ETS-1, EGR, GATA, NFκB, and NR4A. Furthermore, <italic>NFATC1</italic> was directly regulated by ETS-1 at an enhancer region. In contrast to the factors that increased accessibility, signalling from bHLH and ZEB family members enhanced decreased accessibility upon re-stimulation. Interplay between distal regulatory elements, accessibility, and the combined action of sequence-specific transcription factors allows transcriptional memory-responsive genes to “remember” their initial environmental encounter.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Initial T cell stimulation alters the immune gene DNA accessibility landscape with enduring consequences upon stimulus removal.</title><p>(<bold>a</bold>) Schematic of the Jurkat transcriptional memory model. Non-stimulated (NS) Jurkat T cells were stimulated with PMA and ionomycin (ST), washed, and rested (SW) before re-stimulation (RS). (<bold>b</bold>) FAIRE-seq Spearman correlation. (<bold>c,d</bold>) Region with more (<bold>c</bold>) or less (<bold>d</bold>) accessibility in ST, SW, and RS cells compared to NS cells. Sets with altered accessibility in RS and ST were divided according to whether the accessibility was higher (≥1.75) in ST (<sup>1</sup>) or RS (<sup>2</sup>). (<bold>e</bold>) Mean Z-score profiles of the increased accessibility sets. (<bold>f</bold>) Over-represented Gene Ontology biological pathways and KEGG pathways in the genes nearest to the regions with increased or decreased accessibility. (<bold>g</bold>) The expression of genes near SW >NS accessible regions that are upregulated in effector memory (EM), activated memory (AM), naïve Tregs (NT), and memory Tregs (MT) compared to naïve (N) (from E-MEXP-2578). Immune response genes are labelled. Heat map Z-score scaled. (<bold>h</bold>) The percentage of primary response genes (PRG), all genes on the array, and memory-responsive genes (MRG) with transcriptional start sites (TSSs) within 50 kb of a region for the different subsets. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.001, ***<italic>p</italic> < 1 × 10<sup>−5</sup>, compared to all genes on array, Fisher’s exact test.(<bold>i</bold>) Chromatin conformation capture ligation efficiencies indicating interactions between <italic>TNFSF10, DUSP10</italic>, and <italic>BCL6</italic> enhancers and gene TSSs. The contact frequencies of the gene desert region with similar distances were used as a control. 3C-qPCR data were normalised to bacterial artificial chromosome (BAC) clone ligation products (mean ± SEM, n = 4–5 biological replicates, *<italic>p</italic> < 0.05, <italic>t</italic>-test). Interaction frequency should be considered within a treatment relative to the gene desert region and not across treatments.</p></caption><graphic xlink:href="srep44825-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Changes in the chromatin accessibility (CA) landscape occur in regions with enhancer or permissive chromatin environments in primary CD4 lymphocytes.</title><p>(<bold>a</bold>) Regions in the sets with increased chromatin accessibility were annotated by their chromatin state segmentation in CD4<sup>+</sup> memory cells. The chromatin state data were summarised from CD4<sup>+</sup> Roadmap data: quiescent (quies, low level of marks), repressive (repr, H3K27me3), transcription (trans, H3K36me3), enhancer (enh, H3K4me1), permissive (perm, H3K4me3), and heterochromatin (het, H3K9me3). (<bold>b</bold>) H3K4me3, H3K27ac, and H3K4me1levels around the FAIRE peaks in the transcriptional memory sets in naïve (faint line), memory (dark line), and PMA/I stimulated Th (dotted line) lymphocytes. Average profiles are of sequencing tags per 100 bp. (<bold>c</bold>) Detailed chromatin state of the memory regions in naïve (N), memory (M), and PMA/I stimulated Th (S) CD4<sup>+</sup> lymphocytes. Those regions within 50 kb of an MRG TSS are marked with a black line. Transcribed (Tx), Permissive (Tss), Enhancer (Enh). (<bold>d,e</bold>) Fold change in FAIRE chromatin accessibility of CD4<sup>+</sup> memory cells compared to naïve cells (Log2). Naïve (CD4<sup>+</sup> CD45RA<sup>+</sup> CCR7<sup>+</sup> CD27<sup>+</sup>) and memory (CD4<sup>+</sup> CD45RA<sup>−</sup> blood lymphocytes were isolated from 6 donors (biological replicates). Chromatin accessibility was measured by qPCR and normalised to the <italic>PPIA</italic> promoter. Boxplots show median and first to fourth quartiles (*<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, one sample <italic>t</italic>-test against 0).</p></caption><graphic xlink:href="srep44825-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Changes in chromatin accessibility (CA) are associated with altered histone acetylation and variant occupancy and can be remembered through cell division.</title><p>(<bold>a</bold>) ChIP-qPCR analysis of H2A.Z, H2A. Zac, H3, H3.3, H3K27ac, and H3K56ac binding at the <italic>BIRC3</italic> promoter and <italic>TNFSF10</italic> enhancer in the Jurkat model. ChIP enrichment ratio relative to NS is shown (mean ± SEM, n = 3 biological replicates). *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, <italic>t</italic>-test. (<bold>b</bold>) FAIRE chromatin accessibility in the Jurkat model with 6 day resting time. Fold change compared to NS. Chromatin accessibility was normalised to the <italic>GAPDH</italic> promoter (mean ± SEM, n = 3 biological replicates, black * compared to NS, red * ST compared to RS, <italic>t</italic>-test, *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001, ****p < 0.0001).</p></caption><graphic xlink:href="srep44825-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>The transcription factor motifs that characterise the different sets of increased chromatin accessibility (CA).</title><p>(<bold>a</bold>) The top overrepresented motifs in the sets with increased chromatin accessibility. Results from HOMER, *<italic>p</italic> < 0.05, ***<italic>p</italic> < 1 × 10<sup>−5</sup>, Benjamini q value, compared to control sets with similar GC content (trend line). (<bold>b</bold>) The top overrepresented JASPAR motif families in the sets. Enrichment scores >50 (scores shown in brackets) and CLOVER significance p value <0.05 relative to NS regions. (<bold>c</bold>) The relative proportions of the region sets with increased or decreased chromatin accessibility. (<bold>d–i</bold>) The numbers of regions with various JASPAR transcription factor binding motif combinations and their chromatin accessibility sets. Regions of increased chromatin accessibility occur first (clockwise).</p></caption><graphic xlink:href="srep44825-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>The role of ETS-1 in transcriptional memory.</title><p>(<bold>a</bold>) Flow cytometric analysis of ETS-1 expression in peripheral blood lymphocytes, naïve (blue, CD45RO<sup>−</sup>), and memory (filled red, CD45RO<sup>+</sup>) CD4<sup>+</sup> T cells. Cells were left non-stimulated (NS) or stimulated with PMA and calcium ionophore (ST). Dashed lines show isotype control staining. Cells were CD3<sup>+</sup>CD8<sup>−</sup>. A representative of 4 individuals (biological replicates) is shown. (<bold>b</bold>) ETS-1 binding in the memory regulatory regions (SW >NS, sets d-g) in CD4<sup>+</sup> T cells (GSE43119). Sequencing tags were binned by 100 bp and shown ± 5 kb from the centre of the FAIRE region. (<bold>c</bold>) Immunoblot of ETS-1 protein levels in nuclear extracts of NS, ST, SW, and RS cells. ETS-1 intensities were normalised against Novex (protein loading control). A representative of 3 independent biological experiments is shown. (<bold>d</bold>) ETS-1 binding at the <italic>BIRC3</italic> promoter and <italic>TNFSF10</italic> enhancer in the Jurkat model. ChIP enrichment ratio relative to NS. SW cells were rested for 6 days. A representative (mean+/−SEM with n = 3 PCR (technical) repeats) of 3 independent biological experiments is shown. (<bold>e</bold>) ETS-1 protein levels and Novex (protein loading control) in Jurkat cells with mock or <italic>ETS1</italic> siRNA. (<bold>f</bold>) Expression of putative ETS targets in mock or ETS-1 siRNA-treated Jurkat cells. SW cells were rested for 3 days. mRNA levels were measured by RT-PCR and normalised to <italic>GAPDH</italic>. Fold change relative to mock NS is shown. A representative (mean+/−SEM with n = 3 PCR (technical) repeats) of 5 independent biological experiments is shown. (<bold>g</bold>) Chromatin accessibility (CA) of the <italic>BIRC3, MIR21</italic>, and <italic>TNF</italic> promoters and <italic>TNFSF10</italic> and <italic>DUSP10</italic> enhancers in mock or ETS-1 siRNA-treated Jurkat T cells. SW cells were rested for 3 days. Chromatin accessibility was measured by FAIRE-qPCR and normalised to the <italic>GAPDH</italic> promoter. Fold change relative to mock NS. A representative (mean+/−SEM with n = 3 PCR (technical) repeats) of 3 independent biological experiments is shown. (<bold>d,f,g</bold>) *<italic>p</italic> < 0.05, <italic>t</italic>-test.</p></caption><graphic xlink:href="srep44825-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Altering the initial activation signal selectively affects transcriptional memory.</title><p>(<bold>a</bold>) Transcription of <italic>IL2</italic> and <italic>TNF</italic> and chromatin accessibility (CA) of their promoters in the Jurkat TM model with different initial stimuli. Expression levels were measured by RT-PCR and normalised to <italic>GAPDH</italic>. Chromatin accessibility was measured by qPCR and normalised to the <italic>GAPDH</italic> promoter. <italic>IL2</italic> expression values are mean ± SEM, n = 3 biological replicates. For <italic>TNF</italic> expression, values are the average of the RT-PCR (technical) replicates, and error bars indicate min-max. Accessibility: mean ± SEM, n = 3 biological replicates. *<italic>p</italic> < 0.05 compared to NS, <italic>t</italic>-test. (<bold>b</bold>) The regions with altered chromatin accessibility in ST, SW, or RS compared to NS and whether their increase or decrease was rottlerin sensitive (ROTT sens). The regions are coloured by their chromatin accessibility set. (<bold>c</bold>) The chromatin accessibility ratio in RS/ST of all regions with increased accessibility in ST >NS compared to those also SW >NS and those rottlerin sensitive in ST. *<italic>p</italic> < 0.05 compared to all ST >NS, Wilcoxon test. Chromatin accessibility from FAIRE-seq. (<bold>d</bold>) Regions with increased Chromatin accessibility (RS >NS) were analysed for the occurrence of DNA motifs. Regions were ranked according to the ratio of their chromatin accessibility in rottlerin-treated RS cells (compared to DMSO RS), the occurrence of the selected motif is illustrated by black lines and the enrichment score is plotted against the rank of the regions. (<bold>e–f</bold>) The effect of rottlerin (ROTT) pre-treatment on mRNA expression (<bold>e</bold>) and chromatin accessibility (<bold>f</bold>) of the regulatory regions near the gene. Expression levels were measured by RT-PCR and normalised to <italic>GAPDH</italic>. Chromatin accessibility was measured by qPCR and normalised to the <italic>GAPDH</italic> promoter. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, <italic>t</italic>-test, n = 3 biological repeats, mean ± SEM.</p></caption><graphic xlink:href="srep44825-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Cellular localisation and levels of NFATC1 in transcriptional memory and its dependence on PKC.</title><p>(<bold>a</bold>) The nuclear levels of RelA and NFATC1 in P/I stimulated (ST) and re-stimulated (RS) Jurkat cells. (<bold>b</bold>) The nuclear levels of NFATC1 in P/I stimulated (ST) and re-stimulated (RS) Hut-78 cells. (<bold>c</bold>) The nuclear levels of NFATC1 in Jurkat cells pre-treated with DMSO or the PKC-θ-specific kinase inhibitor C27. (<bold>a–c</bold>) Cells were rested for 1 day after the initial stimulation. DAPI co-staining was used. Representative cells for each treatment (10 μm scale bar) are shown, with total nuclear fluorescence intensity (TNFI) from 3 biological replicates with n = 20 cells each, mean ± SEM. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ****<italic>p</italic> < 0.0001. Mann–Whitney test.</p></caption><graphic xlink:href="srep44825-f7"></graphic></fig><fig id="f8"><label>Figure 8</label><caption><title>The role of PKC and ETS-1 in regulating NFATC1.</title><p>(<bold>a</bold>) The effect of rottlerin (ROTT) in the Jurkat transcriptional memory model on DNA accessibility at an <italic>NFATC1</italic> enhancer region. Mean+/− SEM with n = 3 biological repeats. * <italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001. <italic>t</italic>-test. (<bold>b</bold>) ETS-1 binding at the <italic>NFATC1</italic> enhancer region in the Jurkat memory model. Error bars show min-max of 2 PCR values, with the result representative of 3 biological repeats. (<bold>c</bold>,<bold>d</bold>) The effect of <italic>ETS1</italic> siRNA knockdown in the Jurkat transcriptional memory model on accessibility at an <italic>NFATC1</italic> enhancer region (<bold>c</bold>) and <italic>NFATC1</italic> mRNA expression (<bold>d</bold>). Representatives (mean+/−SEM with n = 3 PCR (technical) repeats) of 3 independent biological experiments are shown. (<bold>e</bold>) The nuclear levels of NFATC1 in P/I stimulated (ST), SW, and re-stimulated (RS) Jurkat cells pre-treated with mock or ETS1 siRNA. SW cells were rested for 3 days. Representative cells are shown (10 μm scale bar), with total nuclear fluorescence intensity (TNFI) from 3 biological replicates with n = 20 cells each mean ± SEM. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ****<italic>p</italic> < 0.0001. Mann–Whitney test. (<bold>f</bold>) The memory responsive genes within 50 kb of a region with rottlerin sensitive increased accessibility in RS and that contained a NFAT motif. Regions that also contained ETS-1 motifs are indicated with green lines.</p></caption><graphic xlink:href="srep44825-f8"></graphic></fig><fig id="f9"><label>Figure 9</label><caption><title>Schematic of how transcription factors act in combination to regulate chromatin accessibility (CA) in transcriptional memory.</title><p>In non-stimulated (NS) cells, members of the bHLH, ETS, and TCF7L2 families maintain chromatin accessibility regions. On stimulation (ST), PKC and calcium signalling pathways activate the AP1, EGR, NFκB, NFAT, and NR4A families, which increase accessibility and de-activate some signalling by bHLH members. When stimulus is withdrawn (SW), activation of the induced transcription factors ceases but GATA family members gradually build up and, with ETS family members, maintain a subset of the chromatin accessibility regions and make additional regions accessible. These regions include a potential <italic>NFATC1</italic> enhancer. On re-stimulation (RS), there is re-activation of the induced transcription factors with increased activation of NFκB, NFAT, and NR4A, leading to increased chromatin accessibility at some regions that had increases before and secondary-specific chromatin accessibility at additional regions. The factor ZEB is also activated more upon RS and inhibits accessibility, while differential expression of ID proteins and bHLH members lead to decreases in chromatin accessibility in SW and RS. Weakening of the initial PKC signal by rottlerin (ROTT) partially inhibits chromatin accessibility induced by NFκB and NFAT in the primary and subsequent stimulation. Increased chromatin accessibility marked by x. Purple line represents <italic>NR4A</italic> genes, blue line is <italic>NFATC1</italic> gene.</p></caption><graphic xlink:href="srep44825-f9"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Australie</li><li>France</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Tu, Wen Juan" sort="Tu, Wen Juan" uniqKey="Tu W" first="Wen Juan" last="Tu">Wen Juan Tu</name></noRegion><name sortKey="Denyer, Gareth" sort="Denyer, Gareth" uniqKey="Denyer G" first="Gareth" last="Denyer">Gareth Denyer</name><name sortKey="Dunn, Jenny" sort="Dunn, Jenny" uniqKey="Dunn J" first="Jenny" last="Dunn">Jenny Dunn</name><name sortKey="Hardy, Kristine" sort="Hardy, Kristine" uniqKey="Hardy K" first="Kristine" last="Hardy">Kristine Hardy</name><name sortKey="Khanna, Rajiv" sort="Khanna, Rajiv" uniqKey="Khanna R" first="Rajiv" last="Khanna">Rajiv Khanna</name><name sortKey="Khanna, Rajiv" sort="Khanna, Rajiv" uniqKey="Khanna R" first="Rajiv" last="Khanna">Rajiv Khanna</name><name sortKey="Lee, Sau Kuen" sort="Lee, Sau Kuen" uniqKey="Lee S" first="Sau Kuen" last="Lee">Sau Kuen Lee</name><name sortKey="Lee, Sau Kuen" sort="Lee, Sau Kuen" uniqKey="Lee S" first="Sau Kuen" last="Lee">Sau Kuen Lee</name><name sortKey="Li, Jasmine" sort="Li, Jasmine" uniqKey="Li J" first="Jasmine" last="Li">Jasmine Li</name><name sortKey="Li, Jasmine" sort="Li, Jasmine" uniqKey="Li J" first="Jasmine" last="Li">Jasmine Li</name><name sortKey="Mccuaig, Robert" sort="Mccuaig, Robert" uniqKey="Mccuaig R" first="Robert" last="Mccuaig">Robert Mccuaig</name><name sortKey="Morris, Melanie" sort="Morris, Melanie" uniqKey="Morris M" first="Melanie" last="Morris">Melanie Morris</name><name sortKey="Rao, Sudha" sort="Rao, Sudha" uniqKey="Rao S" first="Sudha" last="Rao">Sudha Rao</name><name sortKey="Smith, Corey" sort="Smith, Corey" uniqKey="Smith C" first="Corey" last="Smith">Corey Smith</name><name sortKey="Smith, Corey" sort="Smith, Corey" uniqKey="Smith C" first="Corey" last="Smith">Corey Smith</name><name sortKey="Sutton, Christopher R" sort="Sutton, Christopher R" uniqKey="Sutton C" first="Christopher R." last="Sutton">Christopher R. Sutton</name><name sortKey="Tan, Abel" sort="Tan, Abel" uniqKey="Tan A" first="Abel" last="Tan">Abel Tan</name><name sortKey="Turner, Stephen J" sort="Turner, Stephen J" uniqKey="Turner S" first="Stephen J." last="Turner">Stephen J. Turner</name><name sortKey="Turner, Stephen J" sort="Turner, Stephen J" uniqKey="Turner S" first="Stephen J." last="Turner">Stephen J. Turner</name></country><country name="France"><noRegion><name sortKey="Brezar, Vedran" sort="Brezar, Vedran" uniqKey="Brezar V" first="Vedran" last="Brezar">Vedran Brezar</name></noRegion><name sortKey="Seddiki, Nabila" sort="Seddiki, Nabila" uniqKey="Seddiki N" first="Nabila" last="Seddiki">Nabila Seddiki</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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