{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T10:59:13Z","timestamp":1776769153182,"version":"3.51.2"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T00:00:00Z","timestamp":1649203200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["R01EB024591"],"award-info":[{"award-number":["R01EB024591"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB-2027949"],"award-info":[{"award-number":["MCB-2027949"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["Newton Award for Transformative Ideas during the COVID-19 Pandemic"],"award-info":[{"award-number":["Newton Award for Transformative Ideas during the COVID-19 Pandemic"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB-2027947"],"award-info":[{"award-number":["MCB-2027947"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008872","name":"Charles Lee Powell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008872","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit\u2019s constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009961","type":"journal-article","created":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T13:37:23Z","timestamp":1649252243000},"page":"e1009961","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Epigenetic cell memory: The gene\u2019s inner chromatin modification circuit"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9235-8226","authenticated-orcid":true,"given":"Simone","family":"Bruno","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-4324","authenticated-orcid":true,"given":"Ruth J.","family":"Williams","sequence":"additional","affiliation":[]},{"given":"Domitilla","family":"Del Vecchio","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"pcbi.1009961.ref001","article-title":"The epigenotype","author":"CH Waddington","year":"1942","journal-title":"Endeavour"},{"key":"pcbi.1009961.ref002","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1305399110","article-title":"Epigenetics: Core misconcept","volume":"110","author":"M Ptashne","year":"2013","journal-title":"Proc. Natl. Acad. Sci"},{"key":"pcbi.1009961.ref003","doi-asserted-by":"crossref","DOI":"10.1038\/nature02089","article-title":"A positive-feedback-based bistable \u2018memory module\u2019 that governs a cell fate decision","volume":"426","author":"W Xiong","year":"2003","journal-title":"Nature"},{"key":"pcbi.1009961.ref004","article-title":"The epigenetic revolution","author":"N Carey","year":"2013","journal-title":"Columbia University Press"},{"key":"pcbi.1009961.ref005","article-title":"Epigenetic Gene Expression and Regulation","author":"S Huang","year":"2015","journal-title":"Academic Press"},{"key":"pcbi.1009961.ref006","article-title":"Essentials of stem cell biology","author":"R Lanza","year":"2014","journal-title":"Elsevier"},{"key":"pcbi.1009961.ref007","doi-asserted-by":"crossref","DOI":"10.1002\/bies.200800189","article-title":"Reprogramming cell fates: reconciling rarity with robustness","volume":"31","author":"S Huang","year":"2009","journal-title":"BioEssays"},{"key":"pcbi.1009961.ref008","doi-asserted-by":"crossref","DOI":"10.1038\/nrg3209","article-title":"Maintaining differentiated cellular identity","volume":"13","author":"J Holmberg","year":"2012","journal-title":"Nature Reviews"},{"issue":"2","key":"pcbi.1009961.ref009","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ydbio.2007.02.036","article-title":"Bifurcation dynamics in lineage-commitment in bipotent progenitor cells","volume":"305","author":"S Huang","year":"2007","journal-title":"Developmental Biology"},{"key":"pcbi.1009961.ref010","volume-title":"Epigenetics","author":"CD Allis","year":"2015"},{"key":"pcbi.1009961.ref011","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2014.02.045","article-title":"Transgenerational Epigenetic Inheritance: Myths and Mechanisms","volume":"157","author":"E Heard","year":"2014","journal-title":"Cell"},{"key":"pcbi.1009961.ref012","doi-asserted-by":"crossref","DOI":"10.1038\/nrg.2016.59","article-title":"The molecular hallmarks of epigenetic control","volume":"17","author":"CD Allis","year":"2016","journal-title":"Nature Reviews"},{"key":"pcbi.1009961.ref013","doi-asserted-by":"crossref","DOI":"10.1126\/science.187.4173.226","article-title":"DNA Modification Mechanisms and Gene Activity during Development","volume":"187","author":"R Holliday","year":"1975","journal-title":"American Association for the Advancement of Science"},{"key":"pcbi.1009961.ref014","doi-asserted-by":"crossref","DOI":"10.1159\/000130315","article-title":"X inactivation, differentiation, and DNA methylation","volume":"14","author":"AD Riggs","year":"1975","journal-title":"Cytogenet Cell Genet"},{"key":"pcbi.1009961.ref015","article-title":"DNA methylation pathways and their crosstalk with histone methylation","volume":"16","author":"J Du","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pcbi.1009961.ref016","doi-asserted-by":"crossref","DOI":"10.1016\/j.stemcr.2015.09.004","article-title":"Efficient recombinase-mediated cassette exchange in hpscs to study the hepatocyte lineage reveals aavs1 locus-mediated transgene inhibition","volume":"5","author":"L Ordovas","year":"2015","journal-title":"Stem Cell Reports"},{"key":"pcbi.1009961.ref017","doi-asserted-by":"crossref","DOI":"10.1080\/02648725.2018.1551594","article-title":"Silencing of transgene expression in mammalian cells by DNA methylation and histone modifications in gene therapy perspective","volume":"35","author":"SY Alhaji","year":"2019","journal-title":"Biotechnology and Genetic Engineering Reviews"},{"key":"pcbi.1009961.ref018","doi-asserted-by":"crossref","DOI":"10.1093\/synbio\/ysaa014","article-title":"Rosa26 docking sites for investigating genetic circuit silencing in stem cells","volume":"5","author":"M Fitzgerald","year":"2020","journal-title":"Synthetic Biology"},{"key":"pcbi.1009961.ref019","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-81975-1","article-title":"Epigenetic silencing directs expression heterogeneity of stably integrated multi\u2011transcript unit genetic circuits","volume":"11","author":"J Zimak","year":"2021","journal-title":"Sci Rep"},{"key":"pcbi.1009961.ref020","doi-asserted-by":"crossref","DOI":"10.1016\/j.coisb.2017.02.003","article-title":"Dissecting chromatin-mediated gene regulation and epigenetic memory through mathematical modelling","volume":"3","author":"L Ringrose","year":"2017","journal-title":"Current Opinion in Systems Biology"},{"key":"pcbi.1009961.ref021","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000785","article-title":"A Model for Genetic and Epigenetic Regulatory Networks Identifies Rare Pathways for Transcription Factor Induced Pluripotency","volume":"6","author":"MN Artyomov","year":"2010","journal-title":"PLOS Comput. Biol"},{"key":"pcbi.1009961.ref022","article-title":"A stochastic model of epigenetic dynamics in somatic cell reprogramming","author":"M Fl\u00f6ttmann","year":"2012","journal-title":"PLOS Comput. Biol"},{"key":"pcbi.1009961.ref023","article-title":"Effects of Collective Histone State Dynamics on Epigenetic Landscape and Kinetics of Cell Reprogramming","author":"SS Ashwin","year":"2015","journal-title":"Nature Reports"},{"issue":"4","key":"pcbi.1009961.ref024","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1080\/15592294.2020.1805686","article-title":"A mathematical model exhibiting the effect of DNA methylation on the stability boundary in cell-fate networks","volume":"16","author":"T Chen","year":"2021","journal-title":"Epigenetics"},{"issue":"6","key":"pcbi.1009961.ref025","article-title":"A possible role for epigenetic feedback regulation in the dynamics of the epithelial-mesenchymal transition (EMT)","volume":"16","author":"W Jia","year":"2019","journal-title":"Phys Biol"},{"key":"pcbi.1009961.ref026","article-title":"Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification","volume":"129","author":"IB Dodd","year":"2007","journal-title":"Cell"},{"key":"pcbi.1009961.ref027","article-title":"The interplay of histone modifications\u2014writers that read","author":"T Zhang","year":"2015","journal-title":"EMBO Reports"},{"key":"pcbi.1009961.ref028","doi-asserted-by":"crossref","DOI":"10.1101\/gad.252103","article-title":"Human Sin3 deacetylase and trithorax-related Set1\/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1","volume":"17","author":"J Wysocka","year":"2003","journal-title":"GENES & DEVELOPMENT"},{"key":"pcbi.1009961.ref029","doi-asserted-by":"crossref","DOI":"10.4161\/epi.5.8.13278","article-title":"Trimethylation of histone H3 lysine 4 impairs methylation of histone H3 lysine 9","volume":"5","author":"O Binda","year":"2010","journal-title":"Epigenetics"},{"issue":"5","key":"pcbi.1009961.ref030","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1177\/1947601910393957","article-title":"DNA Methylation. Superior or Subordinate in the Epigenetic Hierarchy?","volume":"2","author":"B Jin","year":"2011","journal-title":"Genes Cancer"},{"key":"pcbi.1009961.ref031","article-title":"DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA","volume":"448","author":"SKT Ooi","year":"2007","journal-title":"Nature"},{"key":"pcbi.1009961.ref032","article-title":"Mechanisms in Trancriptional Regulation","author":"AJ Courey","year":"2008","journal-title":"Blackwell Publishing"},{"key":"pcbi.1009961.ref033","article-title":"Dimethylation of H3K4 by Set1 Recruits the Set3 Histone Deacetylase Complex to 50 Transcribed Regions","volume":"137","author":"T Kim","year":"2009","journal-title":"Cell"},{"key":"pcbi.1009961.ref034","article-title":"Wdr5 Mediates Self-Renewal and Reprogramming via the Embryonic Stem Cell Core Transcriptional Network","volume":"145","author":"Y Ang","year":"2011","journal-title":"Cell"},{"key":"pcbi.1009961.ref035","doi-asserted-by":"crossref","DOI":"10.1038\/sj.emboj.7600834","article-title":"PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure","volume":"24","author":"T Stopka","year":"2005","journal-title":"The EMBO Journal"},{"key":"pcbi.1009961.ref036","doi-asserted-by":"crossref","DOI":"10.23943\/princeton\/9780691161532.001.0001","volume-title":"Biomolecular Feedback Systems","author":"D Del Vecchio","year":"2014"},{"key":"pcbi.1009961.ref037","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2012.03.052","article-title":"Dynamics and Memory of Heterochromatin in Living Cells","volume":"149","author":"NA Hathaway","year":"2012","journal-title":"Cell"},{"key":"pcbi.1009961.ref038","doi-asserted-by":"crossref","DOI":"10.1186\/s40246-015-0041-3","article-title":"Epigenetic inheritance and the missing heritability","volume":"9","author":"M Trerotola","year":"2015","journal-title":"Human Genomics"},{"key":"pcbi.1009961.ref039","article-title":"Two distinct modes for propagation of histone PTMs across the cell cycle","author":"C Alabert","year":"2015","journal-title":"Research Communication, CSHL"},{"key":"pcbi.1009961.ref040","doi-asserted-by":"crossref","DOI":"10.1016\/j.sbi.2011.08.003","article-title":"Coordinated Methyl-lysine Erasure: Structural and Functional Linkage of a Jumonji demethylasedomain and a Reader domain","volume":"21","author":"AK Upadhyay","year":"2011","journal-title":"Curr Opin Struct Biol"},{"key":"pcbi.1009961.ref041","article-title":"TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells","volume":"42","author":"C Jin","year":"2014","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1009961.ref042","doi-asserted-by":"crossref","DOI":"10.1101\/gad.276568.115","article-title":"Role of TET enzymes in DNA methylation, development, and cancer","volume":"30","author":"KD Rasmussen","year":"2016","journal-title":"GENES & DEVELOPMENT"},{"key":"pcbi.1009961.ref043","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkw1197","article-title":"Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise","volume":"45","author":"AK Ludwig","year":"2017","journal-title":"Nucleic Acid Research"},{"key":"pcbi.1009961.ref044","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.0502036102","article-title":"A population-epigenetic model to infer site-specific methylation rates from double-stranded DNA methylation patterns","volume":"102","author":"DP Genereux","year":"2005","journal-title":"Proc. Natl. Acad. Sci"},{"key":"pcbi.1009961.ref045","doi-asserted-by":"crossref","DOI":"10.1038\/sj.bjc.6604374","article-title":"Proteins that bind methylated DNA and human cancer: reading the wrong words","volume":"98","author":"L Lopez-Serra","year":"2008","journal-title":"British Journal of Cancer"},{"key":"pcbi.1009961.ref046","article-title":"Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex","volume":"393","author":"X Nan","year":"1998","journal-title":"Nature"},{"key":"pcbi.1009961.ref047","doi-asserted-by":"crossref","DOI":"10.1038\/561","article-title":"Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription","volume":"19","author":"PL Jones","year":"1998","journal-title":"Nature Genetics"},{"key":"pcbi.1009961.ref048","doi-asserted-by":"crossref","DOI":"10.1074\/jbc.M210256200","article-title":"The Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation","volume":"278","author":"F Fuks","year":"2003","journal-title":"The J. of Biological Chemistry"},{"key":"pcbi.1009961.ref049","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkg332","article-title":"The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase","volume":"31","author":"F Fuks","year":"2003","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1009961.ref050","doi-asserted-by":"crossref","DOI":"10.1016\/j.pbiomolbio.2010.05.001","article-title":"Structure and Function of SWI\/SNF Chromatin Remodeling Complexes and Mechanistic Implications for Transcription","volume":"102","author":"L Tang","year":"2010","journal-title":"Prog Biophys Mol Biol"},{"key":"pcbi.1009961.ref051","article-title":"Stochastic Simulation of Chemical Kinetics","author":"DT Gillespie","year":"2007","journal-title":"Annual Review of Physical Chemistry"},{"key":"pcbi.1009961.ref052","article-title":"Dynamics of epigenetic regulation at the single-cell level","author":"L Bintu","year":"2016","journal-title":"Science"},{"key":"pcbi.1009961.ref053","doi-asserted-by":"crossref","DOI":"10.1038\/nature08592","article-title":"Direct cell reprogramming is a stochastic process amenable to acceleration","volume":"462","author":"J Hanna","year":"2009","journal-title":"Nature"},{"key":"pcbi.1009961.ref054","article-title":"Deterministic direct reprogramming of somatic cells to pluripotency","author":"Y Rais","year":"2013","journal-title":"Nature"},{"key":"pcbi.1009961.ref055","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","article-title":"Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells","volume":"122","author":"LA Boyer","year":"2005","journal-title":"Cell"},{"key":"pcbi.1009961.ref056","doi-asserted-by":"crossref","DOI":"10.1681\/ASN.2006010083","article-title":"Protein Degradation by the Ubiquitin\u2013Proteasome Pathway in Normal and Disease States","volume":"17","author":"SH Lecker","year":"2006","journal-title":"Journal of the American Society of Nephrology"},{"key":"pcbi.1009961.ref057","doi-asserted-by":"crossref","DOI":"10.1038\/nrm3043","article-title":"Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration","volume":"12","author":"C Jopling","year":"2011","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"pcbi.1009961.ref058","article-title":"Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences","author":"A Cie\u00b4slar-Pobuda","year":"2017","journal-title":"Biochimica et Biophysica Acta (BBA)\u2014Molecular Cell Research"},{"key":"pcbi.1009961.ref059","article-title":"GATA-1 Inhibits PU.1 Gene via DNA and Histone H3K9 Methylation of Its Distal Enhancer in Erythroleukemia","author":"P Burda","year":"2015","journal-title":"PLOS ONE"},{"issue":"2","key":"pcbi.1009961.ref060","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1399-0004.2005.00478.x","article-title":"Genetic regulation of stem cell origins in the mouse embryo","volume":"68","author":"A Ralston","year":"2005","journal-title":"Clinical Genetics"},{"issue":"39","key":"pcbi.1009961.ref061","doi-asserted-by":"crossref","first-page":"14554","DOI":"10.1073\/pnas.0604469103","article-title":"Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi\u2019s sarcoma-associated herpesvirus LANA","volume":"103","author":"M Shamay","year":"2006","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1009961.ref062","article-title":"Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells","volume":"21","author":"Y-H Loh","year":"2007","journal-title":"GENES & DEVELOPMENT"},{"key":"pcbi.1009961.ref063","article-title":"Oct4 and the small molecule inhibitor, SC1, regulates Tet2 expression in mouse embryonic stem cells","volume":"40","author":"Y Wu","year":"2013","journal-title":"Mol Biol Rep"},{"issue":"21","key":"pcbi.1009961.ref064","first-page":"E2889","article-title":"Achieving diverse and monoallelic olfactory receptor selection through dual-objective optimization design","volume":"113","author":"XJ Tian","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009961.ref065","article-title":"Replacement of Oct4 by Tet1 during iPSC Induction Reveals an Important Role of DNA Methylation and Hydroxymethylation in Reprogramming","author":"Y Gao","year":"2013","journal-title":"Cell Stem Cell"},{"key":"pcbi.1009961.ref066","article-title":"Metaplasia and transdifferentiation: from pure biology to the clinic","volume":"8","author":"JMW Slack","year":"2007","journal-title":"Nature Rev. Mol. Cell Bio"},{"key":"pcbi.1009961.ref067","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0018454","article-title":"Activation of neural and pluripotent stem cell signatures correlates with increased malignancy in human glioma","volume":"6","author":"J Holmberg","year":"2011","journal-title":"PLoS ONE"},{"key":"pcbi.1009961.ref068","doi-asserted-by":"crossref","DOI":"10.1038\/s41563-020-00804-4","article-title":"Rethinking organoid technology through bioengineering","volume":"20","author":"E Garreta","year":"2021","journal-title":"Nat. Mater"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009961","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T13:38:33Z","timestamp":1649252313000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009961"}},"subtitle":[],"editor":[{"given":"Carl","family":"Herrmann","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,4,6]]},"references-count":68,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009961","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.02.02.476953","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,6]]}}}