{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T17:28:45Z","timestamp":1770571725604,"version":"3.49.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>We have studied the dynamics of miRNA regulation in two models of circadian oscillators. miRNAs are a class of small RNA molecules (18\u201324 nucleotides) that are known to regulate gene expression at the post-transcriptional level by reducing the amount of proteins produced by translation. This is done either by blocking translation or by degradation of mRNAs, the latter being mainly due to the initiation of a set of processes induced by formation of the miRNA:mRNA complex. Although miRNAs are known to regulate a large number of fundamental biological processes such as growth and development, their role in the dynamics of regulation is not completely understood. In exceptional cases, in particular, they can also up-regulate gene expression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We have studied simple biological systems wherein oscillations originate from negative auto regulation of gene expression. The regulation of gene expression by miRNAs is introduced into these models and the dynamics is studied via standard stochastic simulation techniques. We find that in addition to a reduction in the amplitude of the oscillation, inclusion of miRNAs in the models has the effect of altering the <jats:italic>frequency<\/jats:italic> of oscillation and thereby regulating the dynamics of protein production.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>miRNAs can have a profound effect on the dynamics of regulatory modules, both by control of amplitude, namely by affecting the level of gene expression, as well as by control or alteration of frequency, namely by interference with the temporal sequence of gene production or delivery. We believe that our results are valid for a variety of regulatory systems, beyond the exemplars discussed here.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-3-45","type":"journal-article","created":{"date-parts":[[2009,5,5]],"date-time":"2009-05-05T18:15:01Z","timestamp":1241547301000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["miRNA-regulated dynamics in circadian oscillator models"],"prefix":"10.1186","volume":"3","author":[{"given":"Amitabha","family":"Nandi","sequence":"first","affiliation":[]},{"given":"Candida","family":"Vaz","sequence":"additional","affiliation":[]},{"given":"Alok","family":"Bhattacharya","sequence":"additional","affiliation":[]},{"given":"Ramakrishna","family":"Ramaswamy","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,5,5]]},"reference":[{"key":"313_CR1","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","volume":"116","author":"DP Bartel","year":"2004","unstructured":"Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116: 281-297. 10.1016\/S0092-8674(04)00045-5","journal-title":"Cell"},{"issue":"1","key":"313_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molcel.2005.05.026","volume":"19","author":"VN Kim","year":"2005","unstructured":"Kim VN: Small RNAs: classification, biogenesis, and function. Mol Cells. 2005, 19 (1): 1-15. 10.1016\/j.molcel.2005.05.026","journal-title":"Mol Cells"},{"key":"313_CR3","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nature05983","volume":"448","author":"JG Ruby","year":"2007","unstructured":"Ruby JG, Jan CH, Bartel DP: Intronic microRNA precursors that bypass Drosha processing. Nature. 2007, 448: 83-86. 10.1038\/nature05983","journal-title":"Nature"},{"key":"313_CR4","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1126\/science.1149460","volume":"318","author":"S Vasudevan","year":"2007","unstructured":"Vasudevan S, Tong Y, Steitz JA: Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007, 318: 1931-1934. 10.1126\/science.1149460","journal-title":"Science"},{"key":"313_CR5","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/0092-8674(93)90529-Y","volume":"75","author":"RC Lee","year":"1993","unstructured":"Lee RC, Feinbaum RL, Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993, 75: 843-854. 10.1016\/0092-8674(93)90529-Y","journal-title":"Cell"},{"key":"313_CR6","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/35002607","volume":"403","author":"BJ Reinhart","year":"2000","unstructured":"Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G: The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000, 403: 901-906. 10.1038\/35002607","journal-title":"Nature"},{"key":"313_CR7","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/35040556","volume":"408","author":"AE Pasquinelli","year":"2000","unstructured":"Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, M\u00fcller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000, 408: 86-89. 10.1038\/35040556","journal-title":"Nature"},{"key":"313_CR8","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1101\/gad.1559707","volume":"21","author":"H Siomi","year":"2007","unstructured":"Siomi H, Siomi MC: Expanding RNA physiology: microRNAs in a unicellular organism. Genes Dev. 2007, 21: 1153-1156. 10.1101\/gad.1559707","journal-title":"Genes Dev"},{"key":"313_CR9","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature02871","volume":"431","author":"V Ambros","year":"2004","unstructured":"Ambros V: The functions of animal microRNAs. Nature. 2004, 431: 350-355. 10.1038\/nature02871","journal-title":"Nature"},{"key":"313_CR10","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1038\/nrc1997","volume":"6","author":"GA Calin","year":"2006","unstructured":"Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6: 857-866. 10.1038\/nrc1997","journal-title":"Nat Rev Cancer"},{"key":"313_CR11","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1016\/j.ejca.2007.04.002","volume":"43","author":"EA Wiemer","year":"2007","unstructured":"Wiemer EA: The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007, 43: 1529-1544. 10.1016\/j.ejca.2007.04.002","journal-title":"Eur J Cancer"},{"key":"313_CR12","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.4161\/cc.6.24.5106","volume":"6","author":"HY Cheng","year":"2007","unstructured":"Cheng HY, Obrietan K: Revealing a role of microRNAs in the regulation of the biological clock. Cell Cycle. 2007, 6: 3034-3035.","journal-title":"Cell Cycle"},{"key":"313_CR13","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/1471-2164-9-83","volume":"9","author":"M Yang","year":"2008","unstructured":"Yang M, Lee JE, Padgett RW, Edery I: Circadian regulation of a limited set of conserved microRNAs in Drosophila. BMC Genomics. 2008, 9: 83- 10.1186\/1471-2164-9-83","journal-title":"BMC Genomics"},{"key":"313_CR14","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.neuron.2007.05.017","volume":"54","author":"HY Cheng","year":"2007","unstructured":"Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K: microRNA modulation of circadian-clock period and entrainment. Neuron. 2007, 54: 813-829. 10.1016\/j.neuron.2007.05.017","journal-title":"Neuron"},{"key":"313_CR15","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S0092-8674(00)80566-8","volume":"96","author":"JC Dunlap","year":"1999","unstructured":"Dunlap JC: Molecular bases for circadian clocks. Cell. 1999, 96: 271-290. 10.1016\/S0092-8674(00)80566-8","journal-title":"Cell"},{"key":"313_CR16","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/S0959-437X(98)80017-8","volume":"8","author":"LD Wilsbacher","year":"1998","unstructured":"Wilsbacher LD, Takahashi JS: Circadian rhythms: molecular basis of the clock. Curr Opin Genet Dev. 1998, 8: 595-602. 10.1016\/S0959-437X(98)80017-8","journal-title":"Curr Opin Genet Dev"},{"key":"313_CR17","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1126\/science.1152506","volume":"320","author":"JS O'Neill","year":"2008","unstructured":"O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH: CAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science. 2008, 320: 949-953. 10.1126\/science.1152506","journal-title":"Science"},{"key":"313_CR18","doi-asserted-by":"publisher","first-page":"5988","DOI":"10.1073\/pnas.092133899","volume":"99","author":"JM Vilar","year":"2002","unstructured":"Vilar JM, Kueh HY, Barkai N, Leibler S: Mechanisms of noise-resistance in genetic oscillators. Proc Natl Acad Sci (USA). 2002, 99: 5988-5992. 10.1073\/pnas.092133899.","journal-title":"Proc Natl Acad Sci (USA)"},{"key":"313_CR19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/35002258","volume":"403","author":"N Barkai","year":"2000","unstructured":"Barkai N, Leibler S: Circadian clocks limited by noise. Nature. 2000, 403: 267-268.","journal-title":"Nature"},{"key":"313_CR20","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1073\/pnas.022628299","volume":"99","author":"D Gonze","year":"2002","unstructured":"Gonze D, Halloy J, Goldbeter A: Robustness of circadian rhythms with respect to molecular noise. Proc Natl Acad Sci (USA). 2002, 99: 673-678. 10.1073\/pnas.022628299.","journal-title":"Proc Natl Acad Sci (USA)"},{"key":"313_CR21","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cmet.2006.05.009","volume":"4","author":"J Kr\u00fctzfeldt","year":"2006","unstructured":"Kr\u00fctzfeldt J, Stoffel M: MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 2006, 4: 9-12. 10.1016\/j.cmet.2006.05.009","journal-title":"Cell Metab"},{"key":"313_CR22","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1083\/jcb.200603008","volume":"174","author":"HK Kim","year":"2006","unstructured":"Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A: Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol. 2006, 174: 677-687. 10.1083\/jcb.200603008","journal-title":"J Cell Biol"},{"key":"313_CR23","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1101\/sqb.2006.71.038","volume":"71","author":"SN Bhattacharyya","year":"2006","unstructured":"Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W: Stress-induced reversal of microRNA repression and mRNA P-body localization in human cells. Cold Spring Harb Symp Quant Biol. 2006, 71: 513-521. 10.1101\/sqb.2006.71.038","journal-title":"Cold Spring Harb Symp Quant Biol"},{"key":"313_CR24","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.bbrc.2007.04.207","volume":"358","author":"ZR Xie","year":"2007","unstructured":"Xie ZR, Yang HT, Liu WC, Hwang MJ: The role of microRNA in the delayed negative feedback regulation of gene expression. Biochem Biophys Res Commun. 2007, 358: 722-726. 10.1016\/j.bbrc.2007.04.207","journal-title":"Biochem Biophys Res Commun"},{"key":"313_CR25","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1089\/cmb.2007.0184","volume":"15","author":"R Khanin","year":"2008","unstructured":"Khanin R, Vinciotti V: Computational modeling of post-transcriptional gene regulation by microRNAs. J Comput Biol. 2008, 15: 305-316. 10.1089\/cmb.2007.0184","journal-title":"J Comput Biol"},{"key":"313_CR26","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1016\/S1097-2765(02)00559-2","volume":"9","author":"JD Keene","year":"2002","unstructured":"Keene JD, Tenenbaum SA: Eukaryotic mRNPs may represent posttranscriptional operons. Mol Cell. 2002, 9: 1161-1167. 10.1016\/S1097-2765(02)00559-2","journal-title":"Mol Cell"},{"key":"313_CR27","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1021\/j100540a008","volume":"81","author":"DT Gillespie","year":"1977","unstructured":"Gillespie DT: Exact Stochastic Simulation of Coupled Chemical Reactions. J Phys Chem. 1977, 81: 2340-2361. 10.1021\/j100540a008.","journal-title":"J Phys Chem"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-3-45.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T11:04:14Z","timestamp":1630494254000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-3-45"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,5]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["313"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-3-45","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,5]]},"assertion":[{"value":"6 November 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"45"}}