Transcription Factor AP-1; Programmed Cell Death 1 Receptor; Acetyl Coenzyme A; Mice; Animals; Humans; Transcription Factor AP-1/genetics; Transcription Factor AP-1/metabolism; Programmed Cell Death 1 Receptor/genetics; Programmed Cell Death 1 Receptor/metabolism; Genes, Tumor Suppressor; Acetyl Coenzyme A/metabolism; Glycolysis/genetics; Lymphoma, T-Cell/genetics; Lymphoma, T-Cell, Peripheral; Glycolysis; Lymphoma, T-Cell; Oncology; Cancer Research
Abstract :
[en] The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
Disciplines :
Immunology & infectious disease
Author, co-author :
Wartewig, Tim; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany ; Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA
Daniels, Jay ; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Schulz, Miriam; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Hameister, Erik; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Joshi, Abhinav; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Park, Joonhee; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Morrish, Emma; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany ; German Cancer Consortium (DKTK), Heidelberg, Germany
Venkatasubramani, Anuroop V ; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
Cernilogar, Filippo M ; Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
van Heijster, Frits H A ; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
Hundshammer, Christian; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
Schneider, Heike; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Konstantinidis, Filippos; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Gabler, Judith V; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
Klement, Christine ; Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
KURNIAWAN, Henry ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Law, Calvin ; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Lee, Yujin ; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Choi, Sara; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Guitart, Joan; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Forne, Ignasi ; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
Giustinani, Jérôme; Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France
Müschen, Markus ; Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA ; Department of Immunobiology, Yale University, New Haven, CT, USA
Jain, Salvia; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Weinstock, David M; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA ; Merck Research Laboratories, Boston, MA, USA
Rad, Roland ; Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany ; Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany
Ortonne, Nicolas; Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France ; Pathology Department, AP-HP Inserm U955, Henri Mondor Hospital, Créteil, France
Schilling, Franz ; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
Schotta, Gunnar; Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
Imhof, Axel ; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany
BRENNER, Dirk ; University of Luxembourg ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Choi, Jaehyuk ; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu ; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu ; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. jaehyuk.choi@northwestern.edu ; Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu ; Center for Human Immunobiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu ; Center for Synthetic Biology, Northwestern University, Evanston, IL, USA. jaehyuk.choi@northwestern.edu
Ruland, Jürgen ; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany. j.ruland@tum.de ; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany. j.ruland@tum.de ; German Cancer Consortium (DKTK), Heidelberg, Germany. j.ruland@tum.de ; German Center for Infection Research (DZIF), partner site Munich, Munich, Germany. j.ruland@tum.de
We thank K. Burmeister, A. Doddajjappanavar, V. Höfl, N. Prause, M. Arens, K. Pechloff, W. Lee, Z. Kurgyis, P. Gaulard and A. Wahida for providing excellent technical assistance or helpful discussions and the Core Facility Cell Analysis at TranslaTUM at Klinikum rechts der Isar of the Technical University Munich for their support. We also acknowledge core facilities at Northwestern including the flow cytometry core and the Skin Biology and Disease Resource Center. This work was supported by research grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project ID 210592381, SFB 1054; project ID 360372040, SFB 1335; project ID 395357507, SFB 1371; project ID 369799452, TRR 237; project ID 452881907, TRR 338, RU 695/9-1, RU 695/12-1), The Leukemia & Lymphoma Society and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme awarded grant agreement 834154 to J.R. and grant agreement 820374 to F.S. F.S. was further supported by the DFG (project ID 68647618, SFB 824). J.C. was supported by the National Institutes of Health (1DP2AI136599-01), the American Cancer Society (Research Scholar Grant RSG-20-050-01), the Bakewell Foundation and the Leukemia Lymphoma Society Scholar Award (1377-21). T.W. was supported by the Cancer Research Institute (CRI4029) and is currently funded by NIH–NCI (1K99CA277586-01). J.D. was supported by NIH–NCI grants F30 CA265107 and T32 CA009560.Work in G.S.’s laboratory was funded by the DFG (project ID 213249687, SFB 1064 TP3; project ID 329628492, SFB 1321 TP13). D.B. was supported by FNR CORE grants (C21/BM/15796788 and C18/BM/12691266). M.M. was supported by research grants from the National Institutes of Health (R35CA197628, R01CA157644, R01CA213138 and P01CA233412) and the Howard Hughes Medical Institute (HHMI-55108547). Work in the laboratory of A.I. was funded by research grants from the DFG (project ID 325871075-SFB1309) and the Bundesministerium für Bildung und Forschung (FKZ, FKZ161L0214F, ClinspectM).We thank K. Burmeister, A. Doddajjappanavar, V. Höfl, N. Prause, M. Arens, K. Pechloff, W. Lee, Z. Kurgyis, P. Gaulard and A. Wahida for providing excellent technical assistance or helpful discussions and the Core Facility Cell Analysis at TranslaTUM at Klinikum rechts der Isar of the Technical University Munich for their support. We also acknowledge core facilities at Northwestern including the flow cytometry core and the Skin Biology and Disease Resource Center. This work was supported by research grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project ID 210592381, SFB 1054; project ID 360372040, SFB 1335; project ID 395357507, SFB 1371; project ID 369799452, TRR 237; project ID 452881907, TRR 338, RU 695/9-1, RU 695/12-1), The Leukemia & Lymphoma Society and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme awarded grant agreement 834154 to J.R. and grant agreement 820374 to F.S. F.S. was further supported by the DFG (project ID 68647618, SFB 824). J.C. was supported by the National Institutes of Health (1DP2AI136599-01), the American Cancer Society (Research Scholar Grant RSG-20-050-01), the Bakewell Foundation and the Leukemia Lymphoma Society Scholar Award (1377-21). T.W. was supported by the Cancer Research Institute (CRI4029) and is currently funded by NIH–NCI (1K99CA277586-01). J.D. was supported by NIH–NCI grants F30 CA265107 and T32 CA009560.Work in G.S.’s laboratory was funded by the DFG (project ID 213249687, SFB 1064 TP3; project ID 329628492, SFB 1321 TP13). D.B. was supported by FNR CORE grants (C21/BM/15796788 and C18/BM/12691266). M.M. was supported by research grants from the National Institutes of Health (R35CA197628, R01CA157644, R01CA213138 and P01CA233412) and the Howard Hughes Medical Institute (HHMI-55108547). Work in the laboratory of A.I. was funded by research grants from the DFG (project ID 325871075-SFB1309) and the Bundesministerium für Bildung und Forschung (FKZ, FKZ161L0214F, ClinspectM).
Fiore, D. et al. Peripheral T cell lymphomas: from the bench to the clinic. Nat. Rev. Cancer 20, 323–342 (2020). DOI: 10.1038/s41568-020-0247-0
Park, J. et al. Integrated genomic analyses of cutaneous T cell lymphomas reveal the molecular bases for disease heterogeneity. Blood 138, 1225–1236 (2021).
Anand, K. et al. T-cell lymphoma secondary to checkpoint inhibitor therapy. J. Immunother. Cancer 8, e000104 (2020). DOI: 10.1136/jitc-2019-000104
Marks, J. A., Parker, D. C., Garrot, L. C. & Lechowicz, M. J. Nivolumab-associated cutaneous T-cell lymphoma. JAAD Case Rep. 9, 39–41 (2021). DOI: 10.1016/j.jdcr.2020.12.033
Rauch, D. A. et al. Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood 134, 1406–1414 (2019). DOI: 10.1182/blood.2019002038
Ratner, L., Waldmann, T. A., Janakiram, M. & Brammer, J. E. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N. Engl. J. Med. 378, 1947–1948 (2018). DOI: 10.1056/NEJMc1803181
Bennani, N. N. et al. A phase II study of nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma. Blood 134, 467 (2019). DOI: 10.1182/blood-2019-126194
Patsoukis, N., Li, L., Sari, D., Petkova, V. & Boussiotis, V. A. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33, 3091–3098 (2013). DOI: 10.1128/MCB.00319-13
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016). DOI: 10.1126/science.aae0491
Franco, F., Jaccard, A., Romero, P., Yu, Y. R. & Ho, P. C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. 2, 1001–1012 (2020). DOI: 10.1038/s42255-020-00280-9
Pechloff, K. et al. The fusion kinase ITK–SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J. Exp. Med. 207, 1031–1044 (2010). DOI: 10.1084/jem.20092042
Wartewig, T. et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121–125 (2017). DOI: 10.1038/nature24649
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012). DOI: 10.1038/nri3198
Luo, F. et al. Hypoxia-inducible transcription factor-1α promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway. BMC Cancer 6, 26 (2006). DOI: 10.1186/1471-2407-6-26
Schodel, J. et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP–seq. Blood 117, e207–e217 (2011). DOI: 10.1182/blood-2010-10-314427
Topping, G. J. et al. Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei. MAGMA 33, 221–256 (2020). DOI: 10.1007/s10334-019-00807-6
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009). DOI: 10.1126/science.1160809
Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci 41, 211–218 (2016). DOI: 10.1016/j.tibs.2015.12.001
Warburg, O. Über den Stoffwechsel der Carcinomzelle. Naturwissenschaften 12, 1131–1137 (1924). DOI: 10.1007/BF01504608
Dodd, K. M., Yang, J., Shen, M. H., Sampson, J. R. & Tee, A. R. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34, 2239–2250 (2015). DOI: 10.1038/onc.2014.164
Muschen, M. Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nat. Rev. Immunol. 19, 337–348 (2019). DOI: 10.1038/s41577-019-0154-3
Liu, Q. et al. Development of ATP-competitive mTOR inhibitors. Methods Mol. Biol. 821, 447–460 (2012). DOI: 10.1007/978-1-61779-430-8_29
Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G. & Powis, G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1α. Mol. Cancer Ther. 3, 233–244 (2004). DOI: 10.1158/1535-7163.233.3.3
Yuan, M. et al. Ex vivo and in vivo stable isotope labelling of central carbon metabolism and related pathways with analysis by LC–MS/MS. Nat. Protoc. 14, 313–330 (2019). DOI: 10.1038/s41596-018-0102-x
DeBerardinis, R. J. & Chandel, N. S. We need to talk about the Warburg effect. Nat. Metab. 2, 127–129 (2020). DOI: 10.1038/s42255-020-0172-2
Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16, 694–707 (2016). DOI: 10.1038/nrc.2016.82
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016). DOI: 10.1126/science.aaf6284
Sivanand, S., Viney, I. & Wellen, K. E. Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation. Trends Biochem. Sci. 43, 61–74 (2018). DOI: 10.1016/j.tibs.2017.11.004
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009). DOI: 10.1126/science.1164097
Campbell, S. L. & Wellen, K. E. Metabolic signaling to the nucleus in cancer. Mol. Cell 71, 398–408 (2018). DOI: 10.1016/j.molcel.2018.07.015
Cluntun, A. A. et al. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 3, 10 (2015). DOI: 10.1186/s40170-015-0135-3
Li, J. J. et al. 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg. Med. Chem. Lett. 17, 3208–3211 (2007). DOI: 10.1016/j.bmcl.2007.03.017
Volker-Albert, M. C., Schmidt, A., Forne, I. & Imhof, A. Analysis of histone modifications by mass spectrometry. Curr. Protoc. Protein Sci. 92, e54 (2018). DOI: 10.1002/cpps.54
Icard, P. et al. ATP citrate lyase: a central metabolic enzyme in cancer. Cancer Lett. 471, 125–134 (2020). DOI: 10.1016/j.canlet.2019.12.010
Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014). DOI: 10.1016/j.cmet.2014.06.004
Martinez Calejman, C. et al. mTORC2–AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat. Commun. 11, 575 (2020). DOI: 10.1038/s41467-020-14430-w
Covarrubias, A. J. et al. Akt–mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife 5, e11612 (2016). DOI: 10.7554/eLife.11612
Migita, T. et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 68, 8547–8554 (2008). DOI: 10.1158/0008-5472.CAN-08-1235
Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000). DOI: 10.1021/bi992159y
Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241–5248 (1994). DOI: 10.1016/S0021-9258(17)37680-9
Mardis, E. R. ChIP–seq: welcome to the new frontier. Nat. Methods 4, 613–614 (2007). DOI: 10.1038/nmeth0807-613
Mizzen, C. A. & Allis, C. D. Linking histone acetylation to transcriptional regulation. Cell. Mol. Life Sci. 54, 6–20 (1998). DOI: 10.1007/s000180050121
Kurdistani, S. K., Tavazoie, S. & Grunstein, M. Mapping global histone acetylation patterns to gene expression. Cell 117, 721–733 (2004). DOI: 10.1016/j.cell.2004.05.023
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013). DOI: 10.1038/nmeth.2688
Li, Z. et al. Identification of transcription factor binding sites using ATAC-seq. Genome Biol. 20, 45 (2019). DOI: 10.1186/s13059-019-1642-2
Fornes, O. et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48, D87–D92 (2020).
Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017). DOI: 10.1038/nmeth.4401
Welch, R. P. et al. ChIP-Enrich: gene set enrichment testing for ChIP–seq data. Nucleic Acids Res. 42, e105 (2014). DOI: 10.1093/nar/gku463
Lachmann, A. et al. ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26, 2438–2444 (2010). DOI: 10.1093/bioinformatics/btq466
Consortium, E. P. The ENCODE (Encyclopedia of DNA Elements) Project. Science 306, 636–640 (2004). DOI: 10.1126/science.1105136
Rouillard, A. D. et al. The Harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database 2016, baw100 (2016). DOI: 10.1093/database/baw100
Davis, R. J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000). DOI: 10.1016/S0092-8674(00)00116-1
Sasaki, T. et al. Spatiotemporal regulation of c-Fos by ERK5 and the E3 ubiquitin ligase UBR1, and its biological role. Mol. Cell 24, 63–75 (2006). DOI: 10.1016/j.molcel.2006.08.005
Ferrari, S., Bandi, H. R., Hofsteenge, J., Bussian, B. M. & Thomas, G. Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. J. Biol. Chem. 266, 22770–22775 (1991). DOI: 10.1016/S0021-9258(18)54634-2
Yamada, K., Saito, M., Matsuoka, H. & Inagaki, N. A real-time method of imaging glucose uptake in single, living mammalian cells. Nat. Protoc. 2, 753–762 (2007). DOI: 10.1038/nprot.2007.76
Kim, S. J. et al. A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas. Ann. Oncol. 27, 712–718 (2016). DOI: 10.1093/annonc/mdv624
Yukawa, M. et al. AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation. J. Exp. Med. 217, e20182009 (2020). DOI: 10.1084/jem.20182009
Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019). DOI: 10.1038/s41586-019-1805-z
Qu, K. et al. Chromatin accessibility landscape of cutaneous T cell lymphoma and dynamic response to HDAC inhibitors. Cancer Cell 32, 27–41 (2017). DOI: 10.1016/j.ccell.2017.05.008
Parekh, S., Ziegenhain, C., Vieth, B., Enard, W. & Hellmann, I. The impact of amplification on differential expression analyses by RNA-seq. Sci. Rep. 6, 25533 (2016). DOI: 10.1038/srep25533
Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015). DOI: 10.1016/j.cell.2015.05.002
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). DOI: 10.1186/s13059-014-0550-8
Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003). DOI: 10.1038/ng1180
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005). DOI: 10.1073/pnas.0506580102
Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015). DOI: 10.1016/j.cels.2015.12.004
Shechter, D., Dormann, H. L., Allis, C. D. & Hake, S. B. Extraction, purification and analysis of histones. Nat. Protoc. 2, 1445–1457 (2007). DOI: 10.1038/nprot.2007.202
Yuan, M., Breitkopf, S. B., Yang, X. & Asara, J. M. A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat. Protoc. 7, 872–881 (2012). DOI: 10.1038/nprot.2012.024
MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26, 966–968 (2010). DOI: 10.1093/bioinformatics/btq054
Lauterbach, M. A. et al. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase. Immunity 51, 997–1011 (2019). DOI: 10.1016/j.immuni.2019.11.009
Cernilogar, F. M. et al. Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2. Nucleic Acids Res. 47, 9069–9086 (2019). DOI: 10.1093/nar/gkz627
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009). DOI: 10.1093/bioinformatics/btp324
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012). DOI: 10.1038/nmeth.1923
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009). DOI: 10.1093/bioinformatics/btp352
Tarasov, A., Vilella, A. J., Cuppen, E., Nijman, I. J. & Prins, P. Sambamba: fast processing of NGS alignment formats. Bioinformatics 31, 2032–2034 (2015). DOI: 10.1093/bioinformatics/btv098
Ramirez, F., Dundar, F., Diehl, S., Gruning, B. A. & Manke, T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014). DOI: 10.1093/nar/gku365
Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP–seq enrichment using MACS. Nat. Protoc. 7, 1728–1740 (2012). DOI: 10.1038/nprot.2012.101
Choi, J. et al. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet. 47, 1011–1019 (2015). DOI: 10.1038/ng.3356
Daniels, J. et al. Cellular origins and genetic landscape of cutaneous γ δ T cell lymphomas. Nat. Commun. 11, 1806 (2020). DOI: 10.1038/s41467-020-15572-7
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). DOI: 10.1038/s41586-020-2308-7
Bolotin, D. A. et al. MiXCR: software for comprehensive adaptive immunity profiling. Nat. Methods 12, 380–381 (2015). DOI: 10.1038/nmeth.3364
Corces, M. R. et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods 14, 959–962 (2017). DOI: 10.1038/nmeth.4396
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014). DOI: 10.1093/bioinformatics/btu170
