title: Regulatory network inferred using expression data of small sample size: application and validation in erythroid system.
abstract: BACKGROUND
  Modeling regulatory networks using expression data observed in a differentiation process may help identify context-specific interactions. The outcome of the current algorithms highly depends on the quality and quantity of a single time-course dataset, and the performance may be compromised for datasets with a limited number of samples.
  
  
  RESULTS
  In this work, we report a multi-layer graphical model that is capable of leveraging many publicly available time-course datasets, as well as a cell lineage-specific data with small sample size, to model regulatory networks specific to a differentiation process. First, a collection of network inference methods are used to predict the regulatory relationships in individual public datasets. Then, the inferred directional relationships are weighted and integrated together by evaluating against the cell lineage-specific dataset. To test the accuracy of this algorithm, we collected a time-course RNA-Seq dataset during human erythropoiesis to infer regulatory relationships specific to this differentiation process. The resulting erythroid-specific regulatory network reveals novel regulatory relationships activated in erythropoiesis, which were further validated by genome-wide TR4 binding studies using ChIP-seq. These erythropoiesis-specific regulatory relationships were not identifiable by single dataset-based methods or context-independent integrations. Analysis of the predicted targets reveals that they are all closely associated with hematopoietic lineage differentiation.
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA, Department of Internal Medicine, and Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000465:Algorithms; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D018401:Sample Size; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; D011328:Prions; D014157:Transcription Factors
references.citation: Genome Res. 2011 Mar;21(3):447-55
references.pmid: 21106904
references.citation: Genes Dev. 2007 Nov 1;21(21):2832-44
references.pmid: 17974920
references.citation: Nat Rev Cancer. 2008 Jan;8(1):61-70
references.pmid: 18075512
references.citation: PLoS Comput Biol. 2008 Mar;4(3):e1000044
references.pmid: 18369434
references.citation: Bioinformatics. 2008 Jul 1;24(13):1559-61
references.pmid: 18499696
references.citation: Bioinformatics. 2008 Aug 15;24(16):i76-82
references.pmid: 18689844
references.citation: Oncogene. 2008 Sep 18;27(41):5511-26
references.pmid: 18794885
references.citation: Biosystems. 2009 Apr;96(1):86-103
references.pmid: 19150482
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: BMC Syst Biol. 2009;3:49
references.pmid: 19422680
references.citation: Genome Res. 2011 Jul;21(7):1109-21
references.pmid: 21536720
references.citation: Mol Cell Biol. 2011 Aug;31(16):3298-311
references.pmid: 21670149
references.citation: Sci Signal. 2011 Sep 6;4(189):mr7
references.pmid: 21900204
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D144-9
references.pmid: 22080564
references.citation: Methods Cell Biol. 2012;110:19-56
references.pmid: 22482944
references.citation: Phys Med Biol. 2012 Jun 21;57(12):N183-98
references.pmid: 22617159
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W484-90
references.pmid: 22684505
references.citation: PLoS One. 2012;7(7):e40052
references.pmid: 22815723
references.citation: Nat Methods. 2012 Aug;9(8):796-804
references.pmid: 22796662
references.citation: PLoS Comput Biol. 2012;8(9):e1002694
references.pmid: 23028291
references.citation: Comput Methods Programs Biomed. 2012 Dec;108(3):1012-21
references.pmid: 22824549
references.citation: Bioinformatics. 2013 Jan 15;29(2):246-54
references.pmid: 23175757
references.citation: Nat Med. 2013 Mar;19(3):291-4
references.pmid: 23416702
references.citation: Sci Transl Med. 2013 Apr 17;5(181):181re1
references.pmid: 23596205
references.citation: PLoS Comput Biol. 2014 Mar;10(3):e1003496
references.pmid: 24603430
references.citation: PLoS Genet. 2014 May;10(5):e1004339
references.pmid: 24811540
references.citation: IEEE J Biomed Health Inform. 2013 Sep;17(5):950-8
references.pmid: 25055374
references.citation: Hum Mol Genet. 2014 Sep 1;23(17):4528-42
references.pmid: 24781209
references.citation: Bioinformatics. 2014 Oct;30(19):2772-8
references.pmid: 24919880
references.citation: Bioinformatics. 2014 Dec 1;30(23):3325-33
references.pmid: 25115705
references.citation: PLoS Comput Biol. 2008;4(9):e1000165
references.pmid: 18818725
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1693-8
references.pmid: 11172013
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6163-8
references.pmid: 11983907
references.citation: Curr Opin Plant Biol. 2003 Oct;6(5):410-7
references.pmid: 12972040
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D572-4
references.pmid: 14681483
references.citation: Nat Med. 2004 Aug;10(8):789-99
references.pmid: 15286780
references.citation: Genome Res. 2004 Aug;14(8):1654-63
references.pmid: 15289483
references.citation: J Mol Med (Berl). 1999 Jun;77(6):469-80
references.pmid: 10475062
references.citation: Bioinformatics. 2004 Dec 12;20(18):3594-603
references.pmid: 15284094
references.citation: Bioinformatics. 2005 Jan 1;21(1):71-9
references.pmid: 15308537
references.citation: Nat Biotechnol. 2005 Jan;23(1):69-74
references.pmid: 15619619
references.citation: Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
references.pmid: 16341064
references.citation: Nucleic Acids Res. 2006;34(4):1261-9
references.pmid: 16510852
references.citation: PLoS Biol. 2007 Jan;5(1):e8
references.pmid: 17214507
references.citation: Genome Res. 2009 Jun;19(6):1093-106
references.pmid: 19246570
references.citation: PLoS Comput Biol. 2009 Jun;5(6):e1000417
references.pmid: 19543383
references.citation: Bioinformatics. 2009 Dec 15;25(24):3267-74
references.pmid: 19825796
references.citation: PLoS One. 2010;5(1):e8121
references.pmid: 20126643
references.citation: PLoS One. 2010;5(2):e9202
references.pmid: 20186320
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6286-91
references.pmid: 20308593
references.citation: Nat Biotechnol. 2010 May;28(5):511-5
references.pmid: 20436464
references.citation: Methods Mol Biol. 2010;674:419-41
references.pmid: 20827605
references.citation: PLoS One. 2010;5(9). pii: e12776. doi: 10.1371/journal.pone.0012776
references.pmid: 20927193
references.citation: PLoS Comput Biol. 2010;6(11):e1001009
references.pmid: 21124865
references.citation: PLoS One. 2010;5(12):e14147
references.pmid: 21188141
references.citation: BMC Syst Biol. 2010;4:180
references.pmid: 21194434