{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T13:39:47Z","timestamp":1760708387564},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: We describe a statistical model to dissect the noise in transcriptional bursts in a developmental system.<\/jats:p>\n               <jats:p>Results: We assume that, at any given moment of time, each copy of a native gene inside a cell can exist in either a bursting (active) or non-bursting (inactive) state. The experimentally measured total noise in the transcriptional states of a gene in a population of cells can be mathematically dissected into two contributing components: internal and external. While internal noise quantifies the stochastic nature of transcriptional bursts, external noise is caused by cell-to-cell differences including fluctuations in activator concentration. We use our developed methods to analyze the Drosophila Bicoid (Bcd) morphogen gradient system. For its target gene hunchback (hb), the noise properties can be recapitulated by a simplified gene regulatory model in which Bcd acts as the only input, suggesting that the external noise in hb transcription is primarily derived from fluctuations in the Bcd activator input. However, such a simplified gene regulatory model is insufficient to predict the noise properties of another Bcd target gene, orthodenticle (otd), suggesting that otd transcription is sensitive to additional external fluctuations beyond those in Bcd. Our results show that analysis of the relationship between input and output noise can reveal important insights into how a morphogen gradient system works. Our study also advances the knowledge about transcription at a fundamental level.<\/jats:p>\n               <jats:p>Contact: \u00a0jun.ma@cchmc.org<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/bts068","type":"journal-article","created":{"date-parts":[[2012,2,3]],"date-time":"2012-02-03T01:42:17Z","timestamp":1328233337000},"page":"970-975","source":"Crossref","is-referenced-by-count":15,"title":["Evaluating the <i>Drosophila<\/i> Bicoid morphogen gradient system through dissecting the noise in transcriptional bursts"],"prefix":"10.1093","volume":"28","author":[{"given":"Feng","family":"He","sequence":"first","affiliation":[{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"}]},{"given":"Jie","family":"Ren","sequence":"additional","affiliation":[{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"},{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"},{"name":"1 Division of Biomedical Informatics, 2Division of Developmental Biology, Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA and 3Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, P.R. China"}]}],"member":"286","published-online":{"date-parts":[[2012,2,2]]},"reference":[{"key":"2023012512240569700_B1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1126\/science.1173976","article-title":"Synchronous and stochastic patterns of gene activation in the Drosophila embryo","volume":"325","author":"Boettiger","year":"2009","journal-title":"Science"},{"key":"2023012512240569700_B2","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1242\/dev.064402","article-title":"Scaling of the Bicoid morphogen gradient by a volume-dependent production rate","volume":"138","author":"Cheung","year":"2011","journal-title":"Development"},{"key":"2023012512240569700_B3","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0092-8674(88)90182-1","article-title":"A gradient of bicoid protein in Drosophila embryos","volume":"54","author":"Driever","year":"1988","journal-title":"Cell"},{"key":"2023012512240569700_B4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nature09326","article-title":"Functional roles for noise in genetic circuits","volume":"467","author":"Eldar","year":"2010","journal-title":"Nature"},{"key":"2023012512240569700_B5","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1126\/science.1070919","article-title":"Stochastic gene expression in a single cell","volume":"297","author":"Elowitz","year":"2002","journal-title":"Science"},{"key":"2023012512240569700_B6","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0092-8674(04)00037-6","article-title":"Seeing is believing: the bicoid morphogen gradient matures","volume":"116","author":"Ephrussi","year":"2004","journal-title":"Cell"},{"key":"2023012512240569700_B7","doi-asserted-by":"crossref","first-page":"258101","DOI":"10.1103\/PhysRevLett.103.258101","article-title":"Role of spatial averaging in the precision of gene expression patterns","volume":"103","author":"Erdmann","year":"2009","journal-title":"Phys. Rev. Lett."},{"key":"2023012512240569700_B8","doi-asserted-by":"crossref","first-page":"168302","DOI":"10.1103\/PhysRevLett.97.168302","article-title":"Linking stochastic dynamics to population distribution: an analytical framework of gene expression","volume":"97","author":"Friedman","year":"2006","journal-title":"Phys. Rev. Lett."},{"key":"2023012512240569700_B9","doi-asserted-by":"crossref","first-page":"4185","DOI":"10.1242\/dev.125.21.4185","article-title":"Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen","volume":"125","author":"Gao","year":"1998","journal-title":"Development"},{"key":"2023012512240569700_B10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cell.2007.05.025","article-title":"Probing the limits to positional information","volume":"130","author":"Gregor","year":"2007","journal-title":"Cell"},{"key":"2023012512240569700_B11","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1242\/dev.032409","article-title":"Modelling the Bicoid gradient","volume":"137","author":"Grimm","year":"2010","journal-title":"Development"},{"key":"2023012512240569700_B12","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.devcel.2008.09.004","article-title":"Probing intrinsic properties of a robust morphogen gradient in Drosophila","volume":"15","author":"He","year":"2008","journal-title":"Dev. Cell"},{"key":"2023012512240569700_B13","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.bpj.2010.04.073","article-title":"Shaping a morphogen gradient for positional precision","volume":"99","author":"He","year":"2010","journal-title":"Biophys. J."},{"key":"2023012512240569700_B14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1471-213X-10-80","article-title":"Distance measurements via the morphogen gradient of Bicoid in Drosophila embryos","volume":"10","author":"He","year":"2010","journal-title":"BMC Dev. Biol."},{"key":"2023012512240569700_B15","doi-asserted-by":"crossref","first-page":"e19122","DOI":"10.1371\/journal.pone.0019122","article-title":"A multiscale investigation of bicoid-dependent transcriptional events in Drosophila embryos","volume":"6","author":"He","year":"2011","journal-title":"PLoS One"},{"key":"2023012512240569700_B16","doi-asserted-by":"crossref","first-page":"12167","DOI":"10.1073\/pnas.1018832108","article-title":"Separating intrinsic from extrinsic fluctuations in dynamic biological systems","volume":"108","author":"Hilfinger","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012512240569700_B17","doi-asserted-by":"crossref","first-page":"e1001069","DOI":"10.1371\/journal.pcbi.1001069","article-title":"Gene expression noise in spatial patterning: hunchback promoter structure affects noise amplitude and distribution in Drosophila segmentation","volume":"7","author":"Holloway","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"2023012512240569700_B18","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/415798a","article-title":"Establishment of developmental precision and proportions in the early Drosophila embryo","volume":"415","author":"Houchmandzadeh","year":"2002","journal-title":"Nature"},{"key":"2023012512240569700_B19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.cell.2007.06.038","article-title":"Specifying positional information in the embryo: looking beyond morphogens","volume":"130","author":"Kerszberg","year":"2007","journal-title":"Cell"},{"key":"2023012512240569700_B20","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.devcel.2011.05.009","article-title":"Gene regulation by MAPK substrate competition","volume":"20","author":"Kim","year":"2011","journal-title":"Dev. Cell"},{"key":"2023012512240569700_B21","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/msb.2010.121","article-title":"Substrate-dependent control of MAPK phosphorylation in vivo","volume":"7","author":"Kim","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"2023012512240569700_B22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cell.2007.01.004","article-title":"Morpheus unbound: reimagining the morphogen gradient","volume":"128","author":"Lander","year":"2007","journal-title":"Cell"},{"key":"2023012512240569700_B23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/ncb2141","article-title":"Fates-shifted is an F-box protein that targets Bicoid for degradation and regulates developmental fate determination in Drosophila embryos","volume":"13","author":"Liu","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2023012512240569700_B24","doi-asserted-by":"crossref","first-page":"242","DOI":"10.4161\/fly.5.3.15837","article-title":"Morphogen gradient formation and action: insights from studying Bicoid protein degradation","volume":"5","author":"Liu","year":"2011","journal-title":"Fly (Austin)"},{"key":"2023012512240569700_B25","doi-asserted-by":"crossref","first-page":"21695","DOI":"10.1073\/pnas.0910225106","article-title":"Antagonistic action of Bicoid and the repressor Capicua determines the spatial limits of Drosophila head gene expression domains","volume":"106","author":"Lohr","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012512240569700_B26","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s13238-011-1101-7","article-title":"Transcriptional activators and activation mechanisms","volume":"2","author":"Ma","year":"2011","journal-title":"Protein Cell"},{"key":"2023012512240569700_B27","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nrg1750","article-title":"Filtering transcriptional noise during development: concepts and mechanisms","volume":"7","author":"Martinez","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"2023012512240569700_B28","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1073\/pnas.0807878105","article-title":"Anterior-posterior positional information in the absence of a strong Bicoid gradient","volume":"106","author":"Ochoa-Espinosa","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012512240569700_B29","doi-asserted-by":"crossref","first-page":"e1000486","DOI":"10.1371\/journal.pcbi.1000486","article-title":"Stable, precise, and reproducible patterning of bicoid and hunchback molecules in the early Drosophila embryo","volume":"5","author":"Okabe-Oho","year":"2009","journal-title":"PLoS Comput. Biol."},{"key":"2023012512240569700_B30","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1016\/j.cub.2009.10.028","article-title":"Visualization of individual Scr mRNAs during Drosophila embryogenesis yields evidence for transcriptional bursting","volume":"19","author":"Pare","year":"2009","journal-title":"Curr. Biol."},{"key":"2023012512240569700_B31","doi-asserted-by":"crossref","first-page":"R249","DOI":"10.1016\/j.cub.2010.01.026","article-title":"The bicoid morphogen system","volume":"20","author":"Porcher","year":"2010","journal-title":"Curr. Biol."},{"key":"2023012512240569700_B32","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1242\/dev.051300","article-title":"The time to measure positional information: maternal hunchback is required for the synchrony of the Bicoid transcriptional response at the onset of zygotic transcription","volume":"137","author":"Porcher","year":"2010","journal-title":"Development"},{"key":"2023012512240569700_B33","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1371\/journal.pbio.0040309","article-title":"Stochastic mRNA synthesis in mammalian cells","volume":"4","author":"Raj","year":"2006","journal-title":"PLoS Biol."},{"key":"2023012512240569700_B34","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1126\/science.1098641","article-title":"Control of stochasticity in eukaryotic gene expression","volume":"304","author":"Raser","year":"2004","journal-title":"Science"},{"key":"2023012512240569700_B35","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1126\/science.1105891","article-title":"Noise in gene expression: origins, consequences, and control","volume":"309","author":"Raser","year":"2005","journal-title":"Science"},{"key":"2023012512240569700_B36","doi-asserted-by":"crossref","first-page":"041902","DOI":"10.1103\/PhysRevE.80.041902","article-title":"Morphogen profiles can be optimized to buffer against noise","volume":"80","author":"Saunders","year":"2009","journal-title":"Phys. Rev. E Stat. Nonlin. Soft Matter Phys."},{"key":"2023012512240569700_B37","doi-asserted-by":"crossref","first-page":"12795","DOI":"10.1073\/pnas.162041399","article-title":"Intrinsic and extrinsic contributions to stochasticity in gene expression","volume":"99","author":"Swain","year":"2002","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012512240569700_B38","doi-asserted-by":"crossref","first-page":"8614","DOI":"10.1073\/pnas.151588598","article-title":"Intrinsic noise in gene regulatory networks","volume":"98","author":"Thattai","year":"2001","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012512240569700_B39","doi-asserted-by":"crossref","first-page":"e2774","DOI":"10.1371\/journal.pone.0002774","article-title":"The role of input noise in transcriptional regulation","volume":"3","author":"Tkacik","year":"2008","journal-title":"PLoS One"},{"key":"2023012512240569700_B40","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1126\/science.1178962","article-title":"Noise can induce bimodality in positive transcriptional feedback loops without bistability","volume":"327","author":"To","year":"2010","journal-title":"Science"},{"key":"2023012512240569700_B41","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1371\/journal.pcbi.0030078","article-title":"Fundamental limits to position determination by concentration gradients","volume":"3","author":"Tostevin","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"2023012512240569700_B42","doi-asserted-by":"crossref","first-page":"a001255","DOI":"10.1101\/cshperspect.a001255","article-title":"Morphogen gradient formation","volume":"1","author":"Wartlick","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2023012512240569700_B43","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/S0960-9822(99)80509-0","article-title":"Transcribed genes are localized according to chromosomal position within polarized Drosophila embryonic nuclei","volume":"9","author":"Wilkie","year":"1999","journal-title":"Curr. Biol."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/28\/7\/970\/48881159\/bioinformatics_28_7_970.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/28\/7\/970\/48881159\/bioinformatics_28_7_970.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T15:54:42Z","timestamp":1674662082000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/28\/7\/970\/209966"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,2]]},"references-count":43,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2012,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bts068","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2012,4,1]]},"published":{"date-parts":[[2012,2,2]]}}}