Abstract
Transcriptional memory is characterized by a primed cellular state, induced by an external stimulus that results in an altered expression of primed genes upon re-exposure to the inducing signal. Intriguingly, the primed state is heritably maintained across somatic cell divisions even after the initial stimulus and target gene transcription cease. This phenomenon is widely observed across various organisms and appears to enable cells to retain a memory of external signals, thereby adapting to environmental changes. Signals range from nutrient supplies (food) to a variety of stress signals, including exposure to pathogens (foes), leading to long-term memory such as in the case of trained immunity in plants and mammals. Here, we review these priming phenomena and our current understanding of transcriptional memory. We consider different mechanistic models for how memory can work and discuss existing evidence for potential carriers of memory. Key molecular signatures include: the poising of RNA polymerase II machinery, maintenance of histone marks, as well as alterations in nuclear positioning and long-range chromatin interactions. Finally, we discuss the potential adaptive roles of transcriptional memory in the organismal response to its environment from nutrient sensing to trained immunity.
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References
Brickner DG, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee P-C, Widom J, et al. H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. PLoS Biol. 2007;5:e81.
Kamada R, Yang W, Zhang Y, Patel MC, Yang Y, Ouda R, et al. Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci USA. 2018;115:E9162–71.
Siwek W, Tehrani SSH, Mata JF, Jansen LET. Activation of clustered IFNγ target genes drives cohesin-controlled transcriptional memory. Mol Cell. 2020;80:396–409.e6.
Bheda P. Metabolic transcriptional memory. Mol Metab. 2020;38:100955.
Light WH, Brickner DG, Brand VR, Brickner JH. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Mol Cell. 2010;40:112–25.
Sood V, Cajigas I, D’Urso A, Light WH, Brickner JH. Epigenetic transcriptional memory of GAL genes depends on growth in glucose and the Tup1 transcription factor in Saccharomyces cerevisiae. Genetics. 2017;206:1895–907.
Pascual-Garcia P, Debo B, Aleman JR, Talamas JA, Lan Y, Nguyen NH, et al. Metazoan nuclear pores provide a scaffold for poised genes and mediate induced enhancer-promoter contacts. Mol Cell. 2017;66:63–76.e6.
Heard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell. 2014;157:95–109.
Durrant WE, Dong X. Systemic acquired resistance. Annu Rev Phytopathol. 2004;42:185–209.
Ding Y, Fromm M, Avramova Z. Multiple exposures to drought ‘train’ transcriptional responses in Arabidopsis. Nat Commun. 2012;3:1–9.
Song J, Angel A, Howard M, Dean C. Vernalization—a cold-induced epigenetic switch. J Cell Sci. 2012;125:3723–31.
Lämke J, Brzezinka K, Altmann S, Bäurle I. A hit-and-run heat shock factor governs sustained histone methylation and transcriptional stress memory. EMBO J. 2016;35:162–75.
Naik S, Larsen SB, Gomez NC, Alaverdyan K, Sendoel A, Yuan S, et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature. 2017;550:475–80.
Sohn C, Lee A, Qiao Y, Loupasakis K, Ivashkiv LB, Kalliolias GD. Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 2015;67:86–95.
Gialitakis M, Arampatzi P, Makatounakis T, Papamatheakis J. Gamma interferon-dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies. Mol Cell Biol. 2010;30:2046–56.
Light WH, Freaney J, Sood V, Thompson A, D’Urso A, Horvath CM, et al. A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. PLoS Biol. 2013;11:e1001524.
Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, et al. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013;152:157–71.
Netea MG, Quintin J, van der Meer JWM. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9:355–61.
Netea MG, Joosten LAB, Latz E, Mills KHG, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352:aaf1098.
Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447:972–8.
Novakovic B, Habibi E, Wang S-Y, Arts RJW, Davar R, Megchelenbrink W, et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell. 2016;167:1354–68.e14.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2020;22:2–6.
Natoli G, Ostuni R. Adaptation and memory in immune responses. Nat Immunol. 2019;20:783–92.
Seeley JJ, Ghosh S. Molecular mechanisms of innate memory and tolerance to LPS. J Leukoc Biol. 2017;101:107–19.
Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171:34–57.
Yu JR, Lee CH, Oksuz O, Stafford JM, Reinberg D. PRC2 is high maintenance. Genes Dev. 2019;33:903–35.
Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010;11:285–96.
Reinberg D, Vales LD. Chromatin domains rich in inheritance only certain histone posttranslational modifications qualify as being epigenetic. Science. 2018;361:33–4.
Zacharioudakis I, Gligoris T, Tzamarias D. A yeast catabolic enzyme controls transcriptional memory. Curr Biol. 2007;17:2041–6.
Ptashne M, Gann A. Genes and Signals. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2002.
Ptashne M. Principles of a switch. Nat Chem Biol. 2011;7:484–7.
Ptashne M. Epigenetics: core misconcept. Proc Natl Acad Sci USA. 2013;110:7101–3.
D’Urso A, Takahashi Y-H, Xiong B, Marone J, Coukos R, Randise-Hinchliff C, et al. Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. eLife 2016;5:e16691.
Sump B, Brickner DG, D’Urso A, Kim SH, Brickner JH. Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory. eLife. 2022;11:e77646.
Liu N, Avramova Z. Molecular mechanism of the priming by jasmonic acid of specific dehydration stress response genes in Arabidopsis. Epigenetics Chromatin. 2016;9:1–23.
Larsen SB, Cowley CJ, Sajjath SM, Barrows D, Yang Y, Carroll TS, et al. Establishment, maintenance, and recall of inflammatory memory. Cell Stem Cell. 2021;28:1758–74.e8.
Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010;32:317–28.
Ivashkiv LB. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 2013;34:216–23.
Tehrani SS, Mikulski P, Abdul-Zani I, Mata JF, Siwek W, Jansen LE. STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory. EMBO J. 2023;42:e112259.
Palozola KC, Lerner J, Zaret KS. A changing paradigm of transcriptional memory propagation through mitosis. Nat Rev Mol Cell Biol. 2019;20:55–64.
Zhao Z, Zhang Z, Li J, Dong Q, Xiong J, Li Y, et al. Sustained tnf-α stimulation leads to transcriptional memory that greatly enhances signal sensitivity and robustness. eLife. 2020;9:1–27.
Li B, Zeis P, Alekseenko A, Lin G, Tekkedil MM, Steinmetz LM, et al. Differential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation. Nat Commun. 2023;14:910.
Oamen HP, Lau Y, Caudron F. Prion-like proteins as epigenetic devices of stress adaptation. Exp Cell Res. 2020;396:112262.
Harvey ZH, Chakravarty AK, Futia RA, Jarosz DF. A prion epigenetic switch establishes an active chromatin state. Cell. 2020;180:928–40.e14.
D’Urso A, Brickner JH. Epigenetic transcriptional memory. Curr Genet. 2017;63:435–9.
Bheda P, Aguilar-Gómez D, Becker NB, Becker J, Stavrou E, Kukhtevich I et al. Single-cell tracing dissects regulation of maintenance and inheritance of transcriptional reinduction memory. Mol Cell. 2020;78:915–25.
Pascual-Garcia P, Little SC, Capelson M. Nup98-dependent transcriptional memory is established independently of transcription. eLife. 2022;11:e63404.
Gómez-RodrÃguez M, Jansen LET. Basic properties of epigenetic systems: lessons from the centromere. Curr Opin Genet Dev. 2013;23:219–27.
Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M, et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci. 2001;98:12902–7.
Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12:223–32.
Rasid O, Chevalier C, Camarasa TM-N, Fitting C, Cavaillon J-M, Hamon MA. H3K4me1 supports memory-like NK cells induced by systemic inflammation. Cell Rep. 2019;29:3933–45.e3.
Qiu J, Xu B, Ye D, Ren D, Wang S, Benci JL, et al. Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction. Nat Cancer. 2023;4:43–61.
Halley JE, Kaplan T, Wang AY, Kobor MS, Rine J. Roles for H2A.Z and its acetylation in GAL1 transcription and gene induction, but Not GAL1-transcriptional memory. PLOS Biol. 2010;8:e1000401.
Brzezinka K, Altmann S, Czesnick H, Nicolas P, Gorka M, Benke E, et al. Arabidopsis FORGETTER1 mediates stress-induced chromatin memory through nucleosome remodeling. eLife 2016;5:e17061.
Jeronimo C, Robert F. The mediator complex: at the nexus of RNA polymerase II transcription. Trends Cell Biol. 2017;27:765–83.
Allen BL, Taatjes DJ. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol. 2015;16:155–66.
Andrau J-C, van de Pasch L, Lijnzaad P, Bijma T, Koerkamp MG, van de Peppel J, et al. Genome-wide location of the coactivator mediator: binding without activation and transient Cdk8 interaction on DNA. Mol Cell. 2006;22:179–92.
Luyties O, Taatjes DJ. The Mediator kinase module: an interface between cell signaling and transcription. Trends Biochem Sci. 2022;47:314–27.
Osman S, Mohammad E, Lidschreiber M, Stuetzer A, Bazsó FL, Maier KC, et al. The Cdk8 kinase module regulates interaction of the mediator complex with RNA polymerase II. J Biol Chem. 2021;296:100734.
Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117:1281–3.
Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity. 2013;38:250–62.
Du J, Johnson LM, Jacobsen SE, Patel DJ. DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol. 2015;16:519–32.
Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010;11:204–20.
Seaborne RA, Strauss J, Cocks M, Shepherd S, O’Brien TD, van Someren KA, et al. Human skeletal muscle possesses an epigenetic memory of hypertrophy. Sci Rep. 2018;8:1898.
Turner DC, Seaborne RA, Sharples AP. Comparative transcriptome and methylome analysis in human skeletal muscle anabolism, hypertrophy and epigenetic memory. Sci Rep. 2019;9:4251.
Luna E, Bruce TJA, Roberts MR, Flors V, Ton J. Next-generation systemic acquired resistance. Plant Physiol. 2012;158:844–53.
Iurlaro M, von Meyenn F, Reik W. DNA methylation homeostasis in human and mouse development. Curr Opin Genet Dev. 2017;43:101–9.
Iberg-Badeaux A, Collombet S, Laurent B, van Oevelen C, Chin K-K, Thieffry D, et al. A transcription factor pulse can prime chromatin for heritable transcriptional memory. Mol Cell Biol. 2017;37:e00372-16.
Guan Q, Haroon S, Bravo DG, Will JL, Gasch AP. Cellular memory of acquired stress resistance in Saccharomyces cerevisiae. Genetics. 2012;192:495–505.
Casolari JM, Brown CR, Komili S, West J, Hieronymus H, Silver PA. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell. 2004;117:427–39.
Sood V, Brickner JH. Nuclear pore interactions with the genome. Curr Opin Genet Dev. 2014;25:43–9.
Fanucchi S, Fok ET, Dalla E, Shibayama Y, Börner K, Chang EY, et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet. 2019;51:138–50.
Zee BM, Levin RS, DiMaggio PA, Garcia BA. Global turnover of histone post-translational modifications and variants in human cells. Epigenetics Chromatin. 2010;3:22.
Alabert C, Barth TK, Reverón-Gómez N, Sidoli S, Schmidt A, Jensen ON, et al. Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 2015;29:585–90.
Reverón-Gómez N, González-Aguilera C, Stewart-Morgan KR, Petryk N, Flury V, Graziano S, et al. Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication. Mol Cell. 2018;72:239–49.e5.
Crump NT, Milne TA. Why are so many MLL lysine methyltransferases required for normal mammalian development? Cell Mol Life Sci. 2019;76:2885–98.
Ding Y, Fromm M, Avramova Z. Multiple exposures to drought ‘train’ transcriptional responses in Arabidopsis. Nat Commun. 2012;3:740.
Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA. 1994;271:698–702.
Fox AE, Evans GL, Turner FJ, Schwartz BS, Blaustein A. Stimulation of nonspecific resistance to infection by a crude cell wall preparation from Mycobacterium phlei. J Bacteriol. 1966;92:1.
Metawea B, El-Nashar AR, Kamel I, Kassem W, Shamloul R. Application of viable bacille Calmette-Guérin topically as a potential therapeutic modality in condylomata acuminata: a placebo-controlled study. Urology. 2005;65:247–50.
Qiao Y, Giannopoulou EG, Chan CH, Park S-H, Gong S, Chen J, et al. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling. Immunity. 2013;39:454–69.
Kleinnijenhuis J, Quintin J, Preijers F, Joosten LAB, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci. 2012;109:17537–42.
Lau CM, Adams NM, Geary CD, Weizman O-E, Rapp M, Pritykin Y, et al. Epigenetic control of innate and adaptive immune memory. Nat Immunol. 2018;19:963–72.
Verma D, Parasa VR, Raffetseder J, Martis M, Mehta RB, Netea M, et al. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci Rep. 2017;7:12305.
Netea MG, DomÃnguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20:375–88.
Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18:545–58.
Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172:176–90.e19.
Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature. 2009;457:557–61.
Funding
Work in our lab is supported by a Senior Wellcome Research Fellowship 210645/Z/18/Z to LETJ. SSHT was supported by Fundação para a Ciência e a Tecnologia (FCT) doctoral fellowship PD/BD/128438/2017. PM is the recipient of a Pump-Priming award from the Goodger and Schorstein Scholarships Trust Fund (0011194). PM and SSHT were supported by the Wellcome SRF. AK is a Clarendon Scholar supported by the Hill Foundation.
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SSHT conceived and wrote the initial draft. AK wrote additional sections and designed the figures. PM wrote additional sections and helped direct the writing of the manuscript. LETJ helped design figures and wrote the final version. All authors were involved in literature searches, updating and proofreading the manuscript.
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Tehrani, S.S.H., Kogan, A., Mikulski, P. et al. Remembering foods and foes: emerging principles of transcriptional memory. Cell Death Differ (2023). https://doi.org/10.1038/s41418-023-01200-6
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DOI: https://doi.org/10.1038/s41418-023-01200-6
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