{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:30:12Z","timestamp":1776321012632,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Transcriptional regulatory networks controlling cell fate decisions in mammalian embryonic development remain elusive despite a long time of research. The recent emergence of single-cell RNA profiling technology raises hope for new discovery. Although experimental works have obtained intriguing insights into the mouse early development, a holistic and systematic view is still missing. Mathematical models of cell fates tend to be concept-based, not designed to learn from real data. To elucidate the regulatory mechanisms behind cell fate decisions, it is highly desirable to synthesize the data-driven and knowledge-driven modeling approaches.<\/jats:p>\n               <jats:p>Results: We propose a novel method that integrates the structure of a cell lineage tree with transcriptional patterns from single-cell data. This method adopts probabilistic Boolean network (PBN) for network modeling, and genetic algorithm as search strategy. Guided by the \u2018directionality\u2019 of cell development along branches of the cell lineage tree, our method is able to accurately infer the regulatory circuits from single-cell gene expression data, in a holistic way. Applied on the single-cell transcriptional data of mouse preimplantation development, our algorithm outperforms conventional methods of network inference. Given the network topology, our method can also identify the operational interactions in the gene regulatory network (GRN), corresponding to specific cell fate determination. This is one of the first attempts to infer GRNs from single-cell transcriptional data, incorporating dynamics of cell development along a cell lineage tree.<\/jats:p>\n               <jats:p>Availability and implementation: Implementation of our algorithm is available from the authors upon request.<\/jats:p>\n               <jats:p>Contact: \u00a0zhengjie@ntu.edu.sg<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btu777","type":"journal-article","created":{"date-parts":[[2014,11,22]],"date-time":"2014-11-22T02:58:16Z","timestamp":1416625096000},"page":"1060-1066","source":"Crossref","is-referenced-by-count":47,"title":["Single-cell transcriptional analysis to uncover regulatory circuits driving cell fate decisions in early mouse development"],"prefix":"10.1093","volume":"31","author":[{"given":"Haifen","family":"Chen","sequence":"first","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]},{"given":"Shital K.","family":"Mishra","sequence":"additional","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]},{"given":"Paul","family":"Robson","sequence":"additional","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]},{"given":"Mahesan","family":"Niranjan","sequence":"additional","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"},{"name":"1 School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore, 2Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore and 3School of Electronics and Computer Science, University of Southampton, Highfield, Southampton SO17 1BJ, UK"}]}],"member":"286","published-online":{"date-parts":[[2014,12,9]]},"reference":[{"key":"2023051309142284600_btu777-B1","doi-asserted-by":"crossref","first-page":"e19358","DOI":"10.1371\/journal.pone.0019358","article-title":"A general model for binary cell fate decision gene circuits with degeneracy: indeterminacy and switch behavior in the absence of cooperativity","volume":"6","author":"Andrecut","year":"2011","journal-title":"PLoS One"},{"key":"2023051309142284600_btu777-B2","doi-asserted-by":"crossref","first-page":"i80","DOI":"10.1093\/bioinformatics\/btt243","article-title":"Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model","volume":"29","author":"Bonzanni","year":"2013","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B3","doi-asserted-by":"crossref","first-page":"e1000702","DOI":"10.1371\/journal.pcbi.1000702","article-title":"Mathematical modelling of cell-fate decision in response to death receptor engagement","volume":"6","author":"Calzone","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2023051309142284600_btu777-B4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.devcel.2006.02.020","article-title":"Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway","volume":"10","author":"Chazaud","year":"2006","journal-title":"Develop. Cell"},{"key":"2023051309142284600_btu777-B5","volume-title":"The WinMine Toolkit","author":"Chickering","year":"2002"},{"key":"2023051309142284600_btu777-B6","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1089\/10665270252833208","article-title":"Modeling and simulation of genetic regulatory systems: a literature review","volume":"9","author":"De Jong","year":"2002","journal-title":"J. Comput. Biol."},{"key":"2023051309142284600_btu777-B7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/BF00113894","article-title":"Learning with genetic algorithms: an overview","volume":"3","author":"De Jong","year":"1988","journal-title":"Mach Learn"},{"key":"2023051309142284600_btu777-B8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1142\/S0219720005001004","article-title":"Minimum redundancy feature selection from microarray gene expression data","volume":"3","author":"Ding","year":"2005","journal-title":"J. Bioinform. Comput. Biol."},{"key":"2023051309142284600_btu777-B9","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1093\/bioinformatics\/bts517","article-title":"Static network structure can be used to model the phenotypic effects of perturbations in regulatory networks","volume":"28","author":"Feiglin","year":"2012","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B10","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.devcel.2011.10.019","article-title":"Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling","volume":"21","author":"Frankenberg","year":"2011","journal-title":"Develop. Cell"},{"key":"2023051309142284600_btu777-B11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1752-0509-1-39","article-title":"Modeling gene expression regulatory networks with the sparse vector autoregressive model","volume":"1","author":"Fujita","year":"2007","journal-title":"BMC Syst. Biol."},{"key":"2023051309142284600_btu777-B12","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.devcel.2010.02.012","article-title":"Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst","volume":"18","author":"Guo","year":"2010","journal-title":"Develop. Cell"},{"key":"2023051309142284600_btu777-B13","doi-asserted-by":"crossref","first-page":"i250","DOI":"10.1093\/bioinformatics\/bts204","article-title":"Lineage-based identification of cellular states and expression programs","volume":"28","author":"Hashimoto","year":"2012","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B14","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.biosystems.2008.12.004","article-title":"Gene regulatory network inference: Data integration in dynamic models\u2014a review","volume":"96","author":"Hecker","year":"2009","journal-title":"Biosystems"},{"key":"2023051309142284600_btu777-B15","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/scientificamerican0792-66","article-title":"Genetic algorithms","volume":"267","author":"Holland","year":"1992","journal-title":"Sci. Am."},{"key":"2023051309142284600_btu777-B16","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/ncb3042","article-title":"Single-cell technologies sharpen up mammalian stem cell research","volume":"16","author":"Hoppe","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"2023051309142284600_btu777-B17","doi-asserted-by":"crossref","first-page":"e1000380","DOI":"10.1371\/journal.pbio.1000380","article-title":"Cell lineage determination in state space: a systems view brings flexibility to dogmatic canonical rules","volume":"8","author":"Huang","year":"2010","journal-title":"PLoS Biol."},{"key":"2023051309142284600_btu777-B18","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/978-1-4614-1800-9_35","article-title":"Complex gene regulatory networks\u2013from structure to biological observables: cell fate determination","volume-title":"Computational Complexity: Theory, Techniques, and Applications","author":"Huang","year":"2012"},{"issue":"7","key":"2023051309142284600_btu777-B19","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.semcdb.2009.07.003","article-title":"Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective","volume":"20","author":"Huang","year":"2009","journal-title":"Semin. Cell Develop. Biol."},{"key":"2023051309142284600_btu777-B20","doi-asserted-by":"crossref","first-page":"e12776","DOI":"10.1371\/journal.pone.0012776","article-title":"Inferring regulatory networks from expression data using tree-based methods","volume":"5","author":"Irrthum","year":"2010","journal-title":"PLoS One"},{"key":"2023051309142284600_btu777-B21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/224177a0","article-title":"Homeostasis and differentiation in random genetic control networks","volume":"224","author":"Kauffman","year":"1969","journal-title":"Nature"},{"key":"2023051309142284600_btu777-B22","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1093\/bioinformatics\/bti071","article-title":"Inference of s-system models of genetic networks using a cooperative coevolutionary algorithm","volume":"21","author":"Kimura","year":"2005","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B23","doi-asserted-by":"crossref","first-page":"e1003165","DOI":"10.1371\/journal.pcbi.1003165","article-title":"Quantifying cell fate decisions for differentiation and reprogramming of a human stem cell network: landscape and biological paths","volume":"9","author":"Li","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"2023051309142284600_btu777-B24","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1073\/pnas.0305937101","article-title":"The yeast cell-cycle network is robustly designed","volume":"101","author":"Li","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"2023051309142284600_btu777-B25","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1145\/1835804.1835864","article-title":"Negative correlations in collaboration: concepts and algorithms","volume-title":"Proceedings of the 16th ACM SIGKDD international conference on Knowledge discovery and data mining","author":"Li","year":"2010"},{"key":"2023051309142284600_btu777-B26","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/nrm2766","article-title":"Systems biology of stem cell fate and cellular reprogramming","volume":"10","author":"Macarthur","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023051309142284600_btu777-B27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-3-642-39159-0_2","article-title":"Inferring gene regulatory networks from time-series expressions using Random Forests ensemble","volume-title":"Pattern Recognition in Bioinformatics","author":"Maduranga","year":"2013"},{"key":"2023051309142284600_btu777-B28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1752-0509-8-13","article-title":"Network topology and parameter estimation: from experimental design methods to gene regulatory network kinetics using a community based approach","volume":"8","author":"Meyer","year":"2014","journal-title":"BMC Syst. Biol."},{"key":"2023051309142284600_btu777-B29","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1093\/bioinformatics\/btq124","article-title":"BoolNet\u2014An R package for generation, reconstruction and analysis of Boolean networks","volume":"26","author":"M\u00fcssel","year":"2010","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B30","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.devcel.2009.02.003","article-title":"The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass","volume":"16","author":"Nishioka","year":"2009","journal-title":"Develop. Cell"},{"key":"2023051309142284600_btu777-B31","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.gde.2004.06.004","article-title":"Gene regulatory network controlling embryonic specification in the sea urchin","volume":"14","author":"Oliveri","year":"2004","journal-title":"Curr. Opin. Genet. Develop."},{"key":"2023051309142284600_btu777-B32","doi-asserted-by":"crossref","first-page":"045002","DOI":"10.1088\/1478-3975\/9\/4\/045002","article-title":"Cell fate regulation in early mammalian development","volume":"9","author":"Oron","year":"2012","journal-title":"Phys. Biol."},{"key":"2023051309142284600_btu777-B33","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1093\/bioinformatics\/bti664","article-title":"Generating boolean networks with a prescribed attractor structure","volume":"21","author":"Pal","year":"2005","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B34","doi-asserted-by":"crossref","first-page":"i196","DOI":"10.1093\/bioinformatics\/btr239","article-title":"TREEGL: reverse engineering tree-evolving gene networks underlying developing biological lineages","volume":"27","author":"Parikh","year":"2011","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B35","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1093\/bioinformatics\/btq575","article-title":"State reduction for network intervention in probabilistic boolean networks","volume":"26","author":"Qian","year":"2010","journal-title":"Bioinformatics"},{"key":"2023051309142284600_btu777-B36","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1186\/1471-2105-12-S13-S17","article-title":"Stability of building gene regulatory networks with sparse autoregressive models","volume":"12","author":"Rajapakse","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2023051309142284600_btu777-B37","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1242\/dev.017178","article-title":"Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse","volume":"136","author":"Rossant","year":"2009","journal-title":"Development"},{"key":"2023051309142284600_btu777-B38","doi-asserted-by":"crossref","first-page":"e1000438","DOI":"10.1371\/journal.pcbi.1000438","article-title":"The logic of EGFR\/ErbB signaling: theoretical properties and analysis of high-throughput data","volume":"5","author":"Samaga","year":"2009","journal-title":"PLoS Comput. Biol."},{"key":"2023051309142284600_btu777-B39","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1371\/journal.pcbi.0030144","article-title":"Prediction of gene expression in embryonic structures of Drosophila melanogaster","volume":"3","author":"Samsonova","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"2023051309142284600_btu777-B40","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1186\/1471-2105-8-S6-S9","article-title":"Current approaches to gene regulatory network modelling","volume":"8","author":"Schlitt","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023051309142284600_btu777-B41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1242\/dev.060095","article-title":"Cell fate decisions and axis determination in the early mouse embryo","volume":"139","author":"Takaoka","year":"2012","journal-title":"Development"},{"key":"2023051309142284600_btu777-B42","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1038\/nmeth.1557","article-title":"Development and applications of single-cell transcriptome analysis","volume":"8","author":"Tang","year":"2011","journal-title":"Nat. Methods"},{"key":"2023051309142284600_btu777-B43","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jtbi.2009.06.006","article-title":"Uncovering operational interactions in genetic networks using asynchronous Boolean dynamics","volume":"260","author":"Tournier","year":"2009","journal-title":"J. Theor. Biol."},{"key":"2023051309142284600_btu777-B44","doi-asserted-by":"crossref","first-page":"10610","DOI":"10.1073\/pnas.1305423110","article-title":"Engineering of regulated stochastic cell fate determination","volume":"110","author":"Wu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"2023051309142284600_btu777-B45","doi-asserted-by":"crossref","first-page":"e1003777","DOI":"10.1371\/journal.pcbi.1003777","article-title":"Construction and validation of a regulatory network for pluripotency and self-renewal of mouse embryonic stem cells","volume":"10","author":"Xu","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2023051309142284600_btu777-B46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4419-7037-4_1","article-title":"Early embryonic cell fate decisions in the mouse","volume-title":"The Cell Biology of Stem Cells: Advances in Experimental Medicine and Biology","author":"Yamanaka","year":"2010"},{"key":"2023051309142284600_btu777-B47","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1242\/dev.043471","article-title":"FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst","volume":"137","author":"Yamanaka","year":"2010","journal-title":"Development"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/7\/1060\/50306065\/bioinformatics_31_7_1060.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/7\/1060\/50306065\/bioinformatics_31_7_1060.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T09:15:05Z","timestamp":1683969305000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/7\/1060\/181113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,9]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btu777","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,4,1]]},"published":{"date-parts":[[2014,12,9]]}}}