Time varying causal network reconstruction of a mouse cell cycle.
Causal inference
Cell cycle
Change point detection
Dynamics
Temporal variation
Time series
Time varying network reconstruction
Journal
BMC bioinformatics
ISSN: 1471-2105
Titre abrégé: BMC Bioinformatics
Pays: England
ID NLM: 100965194
Informations de publication
Date de publication:
29 May 2019
29 May 2019
Historique:
received:
01
05
2019
accepted:
13
05
2019
entrez:
31
5
2019
pubmed:
31
5
2019
medline:
12
7
2019
Statut:
epublish
Résumé
Biochemical networks are often described through static or time-averaged measurements of the component macromolecules. Temporal variation in these components plays an important role in both describing the dynamical nature of the network as well as providing insights into causal mechanisms. Few methods exist, specifically for systems with many variables, for analyzing time series data to identify distinct temporal regimes and the corresponding time-varying causal networks and mechanisms. In this study, we use well-constructed temporal transcriptional measurements in a mammalian cell during a cell cycle, to identify dynamical networks and mechanisms describing the cell cycle. The methods we have used and developed in part deal with Granger causality, Vector Autoregression, Estimation Stability with Cross Validation and a nonparametric change point detection algorithm that enable estimating temporally evolving directed networks that provide a comprehensive picture of the crosstalk among different molecular components. We applied our approach to RNA-seq time-course data spanning nearly two cell cycles from Mouse Embryonic Fibroblast (MEF) primary cells. The change-point detection algorithm is able to extract precise information on the duration and timing of cell cycle phases. Using Least Absolute Shrinkage and Selection Operator (LASSO) and Estimation Stability with Cross Validation (ES-CV), we were able to, without any prior biological knowledge, extract information on the phase-specific causal interaction of cell cycle genes, as well as temporal interdependencies of biological mechanisms through a complete cell cycle. The temporal dependence of cellular components we provide in our model goes beyond what is known in the literature. Furthermore, our inference of dynamic interplay of multiple intracellular mechanisms and their temporal dependence on one another can be used to predict time-varying cellular responses, and provide insight on the design of precise experiments for modulating the regulation of the cell cycle.
Sections du résumé
BACKGROUND
BACKGROUND
Biochemical networks are often described through static or time-averaged measurements of the component macromolecules. Temporal variation in these components plays an important role in both describing the dynamical nature of the network as well as providing insights into causal mechanisms. Few methods exist, specifically for systems with many variables, for analyzing time series data to identify distinct temporal regimes and the corresponding time-varying causal networks and mechanisms.
RESULTS
RESULTS
In this study, we use well-constructed temporal transcriptional measurements in a mammalian cell during a cell cycle, to identify dynamical networks and mechanisms describing the cell cycle. The methods we have used and developed in part deal with Granger causality, Vector Autoregression, Estimation Stability with Cross Validation and a nonparametric change point detection algorithm that enable estimating temporally evolving directed networks that provide a comprehensive picture of the crosstalk among different molecular components. We applied our approach to RNA-seq time-course data spanning nearly two cell cycles from Mouse Embryonic Fibroblast (MEF) primary cells. The change-point detection algorithm is able to extract precise information on the duration and timing of cell cycle phases. Using Least Absolute Shrinkage and Selection Operator (LASSO) and Estimation Stability with Cross Validation (ES-CV), we were able to, without any prior biological knowledge, extract information on the phase-specific causal interaction of cell cycle genes, as well as temporal interdependencies of biological mechanisms through a complete cell cycle.
CONCLUSIONS
CONCLUSIONS
The temporal dependence of cellular components we provide in our model goes beyond what is known in the literature. Furthermore, our inference of dynamic interplay of multiple intracellular mechanisms and their temporal dependence on one another can be used to predict time-varying cellular responses, and provide insight on the design of precise experiments for modulating the regulation of the cell cycle.
Identifiants
pubmed: 31142274
doi: 10.1186/s12859-019-2895-1
pii: 10.1186/s12859-019-2895-1
pmc: PMC6542064
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
294Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK097430
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL106579
Pays : United States
Organisme : National Institute of Health
ID : 5R01CA195613-20
Organisme : NLM NIH HHS
ID : R01 LM012595
Pays : United States
Organisme : NIH HHS
ID : R01LM012595, U01 DK097430, U01 CA200147, U01 CA198941, U19 AI090023, R01 HL106579, R01HL108735, R01 HD084633, R01 DK109365
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195613
Pays : United States
Organisme : National Science Foundation
ID : STC-0939370
Organisme : NIDDK NIH HHS
ID : R01 DK109365
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD084633
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200147
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA198941
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI090023
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL108735
Pays : United States
Références
Oncogene. 1999 Apr 8;18(14):2299-309
pubmed: 10327050
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6193-8
pubmed: 10339564
Cell. 1999 Jun 11;97(6):767-77
pubmed: 10380928
Genes Dev. 1999 Jun 15;13(12):1501-12
pubmed: 10385618
Biochem Biophys Res Commun. 1999 Sep 16;263(1):35-40
pubmed: 10486249
Oncogene. 1999 Sep 20;18(38):5311-7
pubmed: 10498883
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
Kidney Int. 1999 Dec;56(6):2085-95
pubmed: 10594784
Genes Dev. 2000 Feb 1;14(3):289-300
pubmed: 10673501
J Biol Chem. 2000 Mar 3;275(9):6337-45
pubmed: 10692433
Mol Cell Biol. 2000 May;20(9):3086-96
pubmed: 10757793
Mol Cell Biol. 2000 Jun;20(11):3795-806
pubmed: 10805723
Curr Biol. 2000 Jun 1;10(11):675-8
pubmed: 10837255
Int J Oncol. 2000 Nov;17(5):897-902
pubmed: 11029489
Bioinformatics. 2000 Aug;16(8):727-34
pubmed: 11099258
J Comput Biol. 2000;7(3-4):601-20
pubmed: 11108481
Nat Cell Biol. 2001 Mar;3(3):289-95
pubmed: 11231579
Mol Biol Cell. 2001 Mar;12(3):551-63
pubmed: 11251070
Science. 2001 Aug 17;293(5533):1320-3
pubmed: 11509732
J Cell Biol. 2001 Sep 3;154(5):925-36
pubmed: 11535616
EMBO J. 2001 Dec 3;20(23):6648-59
pubmed: 11726501
Cell. 2001 Dec 14;107(6):715-26
pubmed: 11747808
Mol Cell Biol. 2002 Apr;22(7):2242-54
pubmed: 11884610
Neoplasia. 2002 Mar-Apr;4(2):171-80
pubmed: 11896572
Mol Biol Cell. 2002 Mar;13(3):755-66
pubmed: 11907259
Nucleic Acids Res. 2002 Apr 15;30(8):1859-67
pubmed: 11937641
Annu Rev Biochem. 2002;71:333-74
pubmed: 12045100
Genetics. 2002 Jun;161(2):721-31
pubmed: 12072468
Oncogene. 2002 Jul 4;21(29):4498-507
pubmed: 12085228
Mol Pharmacol. 2002 Sep;62(3):680-8
pubmed: 12181445
J Cell Biol. 2002 Sep 2;158(5):841-7
pubmed: 12196507
Cancer Cell. 2002 Aug;2(2):103-12
pubmed: 12204530
J Theor Biol. 2002 Oct 7;218(3):331-41
pubmed: 12381434
Oncogene. 2003 Jan 16;22(2):161-7
pubmed: 12527885
Genes Cells. 2003 Feb;8(2):145-61
pubmed: 12581157
J Mol Biol. 2003 Mar 14;327(1):111-28
pubmed: 12614612
J Biol Chem. 2003 Aug 8;278(32):29940-7
pubmed: 12756247
EMBO J. 2003 Aug 15;22(16):4294-303
pubmed: 12912926
Genome Biol. 2003;4(9):117
pubmed: 12952525
Science. 1992 Sep 25;257(5078):1955-7
pubmed: 1384126
Science. 1992 Sep 18;257(5077):1689-94
pubmed: 1388288
Plant Cell. 2004 Jan;16(1):99-113
pubmed: 14660803
J Biol Chem. 2004 Apr 16;279(16):16000-6
pubmed: 14761977
Mol Cell Biol. 2004 Jul;24(14):6268-77
pubmed: 15226429
Bioinformatics. 2005 Jan 1;21(1):71-9
pubmed: 15308537
BMC Bioinformatics. 2004 Aug 31;5:118
pubmed: 15339346
Mol Cell. 2004 Oct 8;16(1):47-58
pubmed: 15469821
Bioinformatics. 2005 Mar;21(6):754-64
pubmed: 15479708
EMBO J. 2004 Dec 8;23(24):4709-16
pubmed: 15538380
Curr Biol. 2005 Feb 8;15(3):214-25
pubmed: 15694304
Dev Biol. 2005 Mar 15;279(2):345-55
pubmed: 15733663
Mol Cell Biol. 2005 May;25(9):3553-62
pubmed: 15831461
Oncogene. 2005 Apr 18;24(17):2827-43
pubmed: 15838518
Mol Cell. 2005 Jul 1;19(1):135-41
pubmed: 15989971
Mol Cell Biol. 2005 Aug;25(16):6937-47
pubmed: 16055707
Genome Biol. 2006;7(2):R11
pubmed: 16507166
Cell. 1991 Oct 4;67(1):189-96
pubmed: 1655274
EMBO J. 1991 Nov;10(11):3297-309
pubmed: 1655416
BMC Bioinformatics. 2006 Mar 20;7 Suppl 1:S7
pubmed: 16723010
Genetics. 2006 Sep;174(1):155-65
pubmed: 16849602
J Biol Chem. 2006 Oct 13;281(41):30631-44
pubmed: 16912045
Stem Cell Rev. 2005;1(2):131-8
pubmed: 17142847
Nat Cell Biol. 2007 Feb;9(2):225-32
pubmed: 17187060
J Biol Chem. 2007 May 18;282(20):15217-27
pubmed: 17376779
Bioinformatics. 2007 Jul 1;23(13):1623-30
pubmed: 17463021
EMBO J. 1991 Dec;10(13):4279-90
pubmed: 1756735
Oncogene. 2008 Apr 17;27(18):2583-93
pubmed: 17982488
J Cell Biol. 2007 Nov 19;179(4):611-7
pubmed: 17998400
Oncogene. 2008 May 29;27(24):3475-82
pubmed: 18084324
Nature. 1991 Feb 28;349(6312):808-11
pubmed: 1825699
J Anat. 2008 Jul;213(1):30-44
pubmed: 18638068
Mol Biol Cell. 2008 Oct;19(10):4374-82
pubmed: 18667534
PLoS Comput Biol. 2008 Aug 15;4(8):e1000117
pubmed: 18704157
Nat Cell Biol. 2008 Dec;10(12):1411-20
pubmed: 18997788
J Cell Biol. 2008 Nov 17;183(4):667-80
pubmed: 19015317
Cell. 1991 Oct 4;67(1):197-211
pubmed: 1913817
Cell Div. 2009 Jan 19;4:2
pubmed: 19152694
Dev Cell. 2009 Jan;16(1):118-31
pubmed: 19154723
Biochim Biophys Acta. 2009 Mar;1793(3):462-8
pubmed: 19185590
Curr Biol. 2009 Mar 10;19(5):369-80
pubmed: 19249208
Cell Cycle. 2009 Apr 1;8(7):1044-52
pubmed: 19270522
Mol Biol Cell. 2009 May;20(10):2626-37
pubmed: 19339280
Oncogene. 2009 Aug 6;28(31):2806-20
pubmed: 19503101
Mol Biosyst. 2009 Dec;5(12):1512-26
pubmed: 20023718
PLoS Comput Biol. 2010 Jan 29;6(1):e1000654
pubmed: 20126526
J Biol Chem. 2010 Jun 11;285(24):18407-14
pubmed: 20308078
Curr Biol. 2010 May 11;20(9):856-60
pubmed: 20399658
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Cell Div. 2010 Aug 27;5:20
pubmed: 20799962
Bioinformatics. 2010 Sep 15;26(18):i517-23
pubmed: 20823316
Cell Cycle. 2010 Nov 15;9(22):4533-41
pubmed: 21088490
J Cell Biol. 2010 Nov 29;191(5):981-97
pubmed: 21098112
Int J Biol Sci. 2010 Nov 24;6(7):700-15
pubmed: 21152263
Nat Cell Biol. 2011 Mar;13(3):223-33
pubmed: 21336306
J Biol Chem. 2011 Apr 22;286(16):14157-67
pubmed: 21362622
J Biol Chem. 2011 Jun 17;286(24):21173-9
pubmed: 21525009
J Orthop Sci. 2011 Nov;16(6):814-20
pubmed: 21901524
J Biol Chem. 2011 Nov 18;286(46):39776-85
pubmed: 21965652
EMBO J. 2011 Nov 01;30(24):4885-96
pubmed: 22045335
J Chem Phys. 2012 Jan 21;136(3):034105
pubmed: 22280742
Nat Rev Genet. 2012 Mar 13;13(4):227-32
pubmed: 22411467
Mol Cell. 2012 May 11;46(3):351-61
pubmed: 22464731
Nat Cell Biol. 2012 Jun 03;14(7):746-52
pubmed: 22660415
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12550-5
pubmed: 22802651
Dev Cell. 2012 Jul 17;23(1):112-23
pubmed: 22814604
IET Syst Biol. 2012 Oct;6(5):155-63
pubmed: 23101870
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Genes Cancer. 2012 Mar;3(3-4):199-208
pubmed: 23150753
PLoS One. 2012;7(11):e50411
pubmed: 23226279
Cell Cycle. 2013 Apr 1;12(7):1083-90
pubmed: 23454898
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Biochem Biophys Res Commun. 2013 Jun 21;436(1):12-8
pubmed: 23643811
Cell. 1990 Feb 23;60(4):665-73
pubmed: 2406029
J Biol Chem. 2013 Dec 6;288(49):35149-58
pubmed: 24151075
Nucleic Acids Res. 2014 Jan;42(Database issue):D472-7
pubmed: 24243840
Genes Dev. 2014 Jan 15;28(2):140-52
pubmed: 24402315
Elife. 2014 Jan 01;3:e01630
pubmed: 24596151
IEEE Trans Biomed Circuits Syst. 2014 Feb;8(1):74-86
pubmed: 24681921
Science. 2014 Oct 24;346(6208):1253596
pubmed: 25342810
Sci Rep. 2015 Mar 11;5:8937
pubmed: 25758050
Oncotarget. 2015 May 30;6(15):13072-87
pubmed: 25965828
J Cell Biol. 2015 May 25;209(4):507-17
pubmed: 25987605
Sci Rep. 2015 Jun 08;5:10775
pubmed: 26053859
BMC Biol. 2015 Jul 01;13:46
pubmed: 26129844
Nucleic Acids Res. 2016 Feb 18;44(3):1133-50
pubmed: 26531827
Sci Rep. 2016 Feb 11;6:20533
pubmed: 26864687
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
NPJ Syst Biol Appl. 2015 Dec 10;1:15016
pubmed: 28725464
J Theor Biol. 1969 Mar;22(3):437-67
pubmed: 5803332
Mol Biol Cell. 1995 Apr;6(4):371-85
pubmed: 7626804
Cell. 1995 May 5;81(3):323-30
pubmed: 7736585
EMBO J. 1995 Apr 18;14(8):1646-54
pubmed: 7737117
Mol Cell Biol. 1995 May;15(5):2536-46
pubmed: 7739537
Mol Cell Biol. 1995 May;15(5):2682-8
pubmed: 7739548
Genes Dev. 1995 Jun 1;9(11):1340-53
pubmed: 7797074
Oncogene. 1995 Jan 5;10(1):177-84
pubmed: 7824270
Cell. 1993 Nov 19;75(4):779-90
pubmed: 8242749
Genes Dev. 1993 Oct;7(10):1850-61
pubmed: 8405995
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3521-4
pubmed: 8475101
J Biol Chem. 1996 Apr 5;271(14):8313-20
pubmed: 8626527
J Cell Sci Suppl. 1995;19:91-4
pubmed: 8655653
Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10321-6
pubmed: 8816798
J Cell Physiol. 1996 Sep;168(3):510-20
pubmed: 8816905
EMBO J. 1997 Feb 3;16(3):545-54
pubmed: 9034337
Gene. 1997 Mar 18;187(2):239-46
pubmed: 9099887
J Cell Physiol. 1997 Aug;172(2):265-73
pubmed: 9258347
J Biol Chem. 1997 Aug 29;272(35):22300-6
pubmed: 9268380
Cell. 1997 Aug 22;90(4):649-60
pubmed: 9288745
Cell. 1997 Oct 3;91(1):59-69
pubmed: 9335335
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3603-8
pubmed: 9520412
Cell. 1998 Mar 20;92(6):713-23
pubmed: 9529248
Cell. 1998 Mar 20;92(6):725-34
pubmed: 9529249
Curr Opin Genet Dev. 1998 Feb;8(1):28-35
pubmed: 9529602
Science. 1998 Apr 24;280(5363):593-6
pubmed: 9554851
Mol Cell Biol. 1998 May;18(5):2758-67
pubmed: 9566895
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8292-7
pubmed: 9653180
Oncogene. 1998 Oct 8;17(14):1777-85
pubmed: 9778043
EMBO J. 1999 Jan 15;18(2):396-410
pubmed: 9889196