Cell Mol Neurobiol (2011) 31:233–241 DOI 10.1007/s10571-010-9613-x
ORIGINAL RESEARCH
MYBPC1 Computational Phosphoprotein Network Construction and Analysis between Frontal Cortex of HIV encephalitis (HIVE) and HIVE-Control Patients Lin Wang • Juxiang Huang • Minghu Jiang Lingjun Sun
•
Received: 19 May 2010 / Accepted: 7 October 2010 / Published online: 9 November 2010 Ó Springer Science+Business Media, LLC 2010
Abstract MYBPC1 computational phosphoprotein network construction and analysis of frontal cortex of HIV encephalitis (HIVE) was very useful to identify novel markers and potential targets for prognosis and therapy. Based on integrated gene regulatory network infer method by linear programming and a decomposition procedure with analysis of the significant function cluster using kappa statistics and fuzzy heuristic clustering from the database for annotation, visualization, and integrated discovery, we identified and constructed significant molecule MYBPC1 phosphoprotein network from 12 frontal cortex of HIVEcontrol patients and 16 HIVE in the same GEO Dataset GDS1726. Our result verified MYBPC1 phosphoprotein module only in the upstream of frontal cortex of HIVEcontrol patients (CREB5, MAPKAPK3 inhibition), whereas in the upstream of frontal cortex of HIVE (CREB5, ZC3HAV1 activation; ROR1 inhibition) and downstream (MAPKAPK3 activation; CFDP1, PDCD4, RBBP6 inhibition). Importantly, we determined that MYBPC1 phosphoprotein cluster of HIVE was involved in signal transduction, transferase, post-translational protein modification, developmental process and glycoprotein (only in HIVE terms), the condition was vital to inflammation and
Lin Wang, Juxiang Huang, and Minghu Jiang contributed equally to this study. L. Wang (&) J. Huang L. Sun Biomedical Center, School of Electronics Engineering, Beijing University of Posts and Telecommunications, Beijing 100876, China e-mail:
[email protected] M. Jiang Lab of Computational Linguistics, School of Humanities and Social Sciences, Tsinghua University, Beijing 100084, China
cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE included phosphoprotein, organelle, response to stimulus, nucleic acid binding, primary metabolic process, and biological regulation, and these terms were more relative to inflammation and cognition impairment, therefore, we deduced the stronger MYBPC1 phosphoprotein network in HIVE. It would be necessary of the stronger MYBPC1 phosphoprotein function to inflammation and cognition impairment of HIVE. Keywords MYBPC1 HIV encephalitis (HIVE) Computational phosphoprotein network construction and analysis
Introduction The neurodegenerative process in HIV encephalitis (HIVE) was associated with cognitive impairment with extensive damage to the dendritic and synaptic structure. Several mechanisms might be involved in including release of neurotoxins, oxidative stress, and decreased activity of neurotrophic factors (Masliah et al. 2004). The effect of HIV on brain had been studied by several researchers. Such as, decreased brain dopamine transporters were related to cognitive deficits in HIV patients with or without cocaine abuse; Magnetic resonance imaging and spectroscopy of the brain in HIV disease; Analysis of the effects of injecting drug used and HIV-1 infection on 18F-FDG PET brain phosphoprotein (Chang et al. 2008; Descamps et al. 2008; Georgiou et al. 2008). MYBPC1 computational phosphoprotein network construction and analysis of the frontal cortex of HIVE was very useful to identify novel markers and potential targets for prognosis and therapy.
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MYBPC1 was 1 out of 50 genes identified as high expression in the frontal cortex of HIVE versus HIVEcontrol patients. MYBPC1’s molecular function consisted of actin binding, structural molecule activity, cytoskeletal phosphoprotein, structural constituent of muscle and titin binding, and it was involved in biological process of muscle system process, muscle contraction, cell adhesion, and biological adhesion (DAVID database). MYBPC1’s relational study also could be presented in this article (Wu et al. 2004). However, the molecular mechanism concerning MYBPC1 phosphoprotein construction in HIVE had little been addressed. In this article, based on integrated gene regulatory network infer (GRNInfer) method by linear programming and a decomposition procedure with analysis of the significant function cluster using kappa statistics and fuzzy heuristic clustering from DAVID (2010 version), we identified and constructed significant molecule MYBPC1 phosphoprotein network from 12 frontal cortex of HIVE-control patients and 16 HIVE in the same GEO Dataset GDS1726. Our result verified MYBPC1 phosphoprotein module only in the upstream of frontal cortex of HIVE-control patients (CREB5, MAPKAPK3 inhibition), whereas in the upstream of frontal cortex of HIVE (CREB5, ZC3HAV1 activation; ROR1 inhibition) and downstream (MAPKAPK3 activation; CFDP1, PDCD4, RBBP6 inhibition). Importantly, we determined that MYBPC1 phosphoprotein cluster of HIVE is involved in signal transduction, transferase, post-translational protein modification, developmental process and glycoprotein (only in HIVE terms), the condition was vital to inflammation and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVEcontrol patients and HIVE included phosphoprotein, organelle, response to stimulus, nucleic acid binding, primary metabolic process, and biological regulation, and these terms were more relative to inflammation and cognition impairment, therefore, we deduced the stronger MYBPC1 phosphoprotein network in HIVE. It would be necessary of the stronger MYBPC1 phosphoprotein function to inflammation and cognition impairment of HIVE. MYBPC1 phosphoprotein interaction module construction in HIVE could be a new route for studying the pathogenesis of HIVE. Our construction of MYBPC1 phosphoprotein network may be useful to identify novel markers and potential targets for prognosis and therapy of HIVE.
Materials and Methods Microarray Data We used microarrays containing 12558 genes from 12 frontal cortex of HIVE-control patients and 16 HIVE in the
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same GEO Dataset GDS1726 (http://www.ncbi.nlm.nih. gov/sites/GDSbrowser?acc=GDS1726) (Masliah et al. 2004). HIVE-control patients meaned normal adjacent frontal cortex tissues of HIVE and no extensive damage to the dendritic and synaptic structure. Gene Selection Algorithms 50 molecular markers of the frontal cortex of HIVE were identified using significant analysis of microarrays (SAM). SAM was a statistical technique for finding significant genes in a set of microarray experiments. The input to SAM was gene expression measurements from a set of microarray experiments, as well as a response variable from each experiment. The response variable may be a grouping like untreated, treated, and so on. SAM computed a statistic di for each gene i, measuring the strength of the relationship between gene expression and the response variable. It used repeated permutations of the data to determine if the expression of any genes was significantly related to the response. The cutoff for significance was determined by a tuning parameter delta, chosen by the user based on the falsepositive rate. We normalized data by log2, and selected two class unpaired and minimum fold change = 1.52. Here, we chose the 50 top-fold significant (high expression genes of HIVE compared with HIVE-control patients) genes under the false-discovery rate and q-value as 9.12%. The q-value [invented by John Storey (Storey 2002)] was like the wellknown P-value, but adapted to multiple-testing situations. Network Establishment of Candidate Genes The entire network was constructed using GRNInfer (Wang et al. 2006) and GVedit tools. GRNInfer was a novel mathematic method called GNR (Gene Network Reconstruction tool) based on linear programming and a decomposition procedure for inferring gene networks. The method theoretically ensured the derivation of the most consistent network structure with respect to all of the datasets, thereby not only significantly alleviating the problem of data scarcity but also remarkably improving the reconstruction reliability. The following Eq. (1) represented all of the possible networks for the same dataset. ^
J ¼ ðX 0 AÞUK1 V T þ YV T ¼ J þYV T
ð1Þ
We established network based on the 50 top-fold distinguished genes and selected parameters as lambda 0.0 because we used one dataset, threshold 0.000001. Lambda was a positive parameter, which balanced the matching and sparsity terms in the objective function. Using different thresholds, we could predict various networks with different edge densities.
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Functional Annotation Clustering
modules mainly coverd phosphoprotein module (CREB5, ZC3HAV1, ROR1, MYBPC1). In frontal cortex of HIVEcontrol patients, MYBPC1 downstream modules showed little results without phosphoprotein module. In frontal cortex of HIVE, MYBPC1 downstream modules mainly contained phosphoprotein module (MAPKAPK3, CFDP1, PDCD4, RBBP6, MYBPC1), as shown in Table 2. MYBPC1 phosphoprotein cluster terms only in frontal cortex of HIVE-control patients showed no result. However, MYBPC1 phosphoprotein cluster terms only in frontal cortex of HIVE contained signal transduction, transferase, post-translational protein modification, developmental process and glycoprotein. MYBPC1 phosphoprotein cluster terms both in frontal cortex of HIVE-control patients and HIVE included phosphoprotein, organelle, response to stimulus, nucleic acid binding, primary metabolic process, and biological regulation, as shown in Table 3.
The DAVID Gene Functional Clustering Tool provided typical batch annotation and gene-GO term enrichment analysis for highly throughput genes by classifying them into gene groups based on their annotation term cooccurrence (Huang da et al. 2007; Dennis et al. 2003). The grouping algorithm was based on the hypothesis that similar annotations should have similar gene members. The functional annotation clustering integrated the same techniques of kappa statistics to measure the degree of the common genes between two annotations, and fuzzy heuristic clustering to classify the groups of similar annotations according to kappa values.
Results Identification of HIVE Molecular Markers MYBPC1 was 1 out of 50 genes identified as high expression in the frontal cortex of HIVE versus HIVEcontrol patients. We normalized data by log2, and selected two class unpaired and minimum fold change = 1.52. Here, we chose the 50 top-fold significant (high expression genes of HIVE compared with HIVE-control patients) genes under the false-discovery rate and q-value as 9.12%. We identified potential HIVE molecular markers and chose the 50 top-fold significant positive genes from 12558 genes from 12 frontal cortex of HIVE-control patients and 16 HIVE in the same GEO Dataset GDS1726 including myosin binding protein C slow type (MYBPC1), cAMP responsive element binding protein 5 (CREB5), receptor tyrosine kinase-like orphan receptor 1 (ROR1), zinc finger CCCH-type antiviral 1 (ZC3HAV1), mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), craniofacial development protein 1 (CFDP1), programmed cell death 4 (PDCD4), retinoblastoma binding protein 6 (RBBP6), etc. (see abbreviations Table 1). Identification of MYBPC1 Upstream and Downstream Phosphoprotein Cluster in Frontal Cortex of HIVE-Control Patients and HIVE by DAVID We first determined four lists of MYBPC1 up and downstream genes from 12 frontal cortex of HIVE-control patients and 16 HIVE by GRNInfer, respectively. With inputting four lists into DAVID, we further identified MYBPC1 up and downstream phosphoprotein cluster of HIVE-control patients and HIVE. In frontal cortex of HIVE-control patients, MYBPC1 upstream modules mainly included phosphoprotein module (CREB5, MAPKAPK3, MYBPC1). In frontal cortex of HIVE, MYBPC1 upstream
MYBPC1 Upstream and Downstream Phosphoprotein Network Construction in Frontal Cortex of HIVEControl Patients and HIVE In frontal cortex of HIVE-control patients, MYBPC1 upstream phosphoprotein network appeared that CREB5, MAPKAPK3 inhibited MYBPC1, as shown in Fig. 1a, whereas in frontal cortex of HIVE, MYBPC1 upstream phosphoprotein network showed that CREB5, ZC3HAV1 activated MYBPC1, and ROR1 inhibited MYBPC1, as shown in Fig. 1b. In frontal cortex of HIVE-control patients, MYBPC1 downstream phosphoprotein network reflected no result, as shown in Fig. 1c, whereas in frontal cortex of HIVE, MYBPC1 downstream phosphoprotein network appeared that MYBPC1 activated MAPKAPK3 and inhibited CFDP1, PDCD4, RBBP6, as shown in Fig. 1d.
Discussion We have already done some studies in this relative field about gene network construction and analysis presented in our published articles (Sun et al. 2009, 2008; Wang et al. 2010a, b, 2009a, b). Based on integrated gene regulatory network infer method by linear programming and a decomposition procedure with analysis of the significant function cluster using kappa statistics and fuzzy heuristic clustering from the database for annotation, visualization, and integrated discovery, we constructed significant molecule MYBPC1 phosphoprotein network and identified only terms in HIVE-control, only terms in HIVE, both in HIVEcontrol patients and HIVE, respectively. In MYBPC1 phosphoprotein module of upstream network of frontal cortex of HIVE-control patients, our
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236 Table 1 List of abbreviations
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Gene symbol
Gene name
Fold change
q-value (%)
TNFRSF11B
Tumor necrosis factor receptor superfamily member 11b
4.4803508
0
OAS1
20 ,50 -oligoadenylate synthetase 1
3.9355509
0
BTN3A2
Butyrophilin subfamily 3 member A2
3.9301556
0
IFI44L
Interferon-induced protein 44-like
3.5441336
5.38809
ADH1B
Alcohol dehydrogenase 1B (class I) beta polypeptide
3.2670867
0
RASGRP3
RAS guanyl releasing protein 3
AF075680
6.871767 9.118306 0
ISG15
ISG15 ubiquitin-like modifier
2.6613333
ISG15
ISG15 ubiquitin-like modifier
2.6345374
9.031465
MAPKAPK3
Mitogen-activated protein kinase-activated protein kinase 3
2.5681395
6.871767
CREB5
cAMP responsive element binding protein 5
2.4307704
0
MX1
Myxovirus resistance 1 interferon-inducible protein p78
2.303681
9.031465
IFITM1
Interferon-induced transmembrane protein 1
2.2888192
4.390296
MYBPC1
Myosin binding protein C slow type
2.2694294
0
ROR1
Receptor tyrosine kinase-like orphan receptor 1
2.2577143
4.390296
IFI35
Interferon-induced protein 35
2.222163
0
LSM7
LSM7 homolog U6 small nuclear RNA associated
2.2139792
0
LCAT
Lecithin-cholesterol acyltransferase
2.1539339
9.118306
ZC3HAV1
Zinc finger CCCH-type antiviral 1
2.1109323
9.031465
LY96
Lymphocyte antigen 96
2.1098849
0
TSPAN4
Tetraspanin 4
2.0978048
9.031465
C10orf116
Chromosome 10 open reading frame 116
2.0928623
4.390296
DGKG
Diacylglycerol kinase gamma
2.0875982
9.118306
STAT1
Signal transducer and activator of transcription 1
2.0751179
5.38809
IFI27
Interferon alpha-inducible protein 27
2.0552708
0
BST2
Bone marrow stromal cell antigen 2
2.0392547
9.118306
TGFBR3
Transforming growth factor, beta receptor III
2.0160105
0
SLC16A4
Solute carrier family 16 member 4
1.9981528
9.031465
FER1L3
Myoferlin
1.9738948
0
ZNF652
Zinc finger protein 652
1.9546128
9.031465
HLA-B
Hypothetical protein LOC441528
1.9372372
9.118306
PDCD4
Programmed cell death 4
1.9344621
9.118306
SF1
Splicing factor 1
1.9331922
0
AL080060
1.9189894
6.871767
CFHR1
Complement factor H-related 1
1.8322684
9.118306
CFB
Complement factor B
1.8226096
9.118306
LGALS3BP
Lectin galactoside-binding soluble 3 binding protein
1.8100076
9.031465
CD99
CD99 molecule
1.7944883
9.118306
RDX
Radixin
1.7632773
9.118306
MT1G
Metallothionein 1G
1.7460259
5.38809
RBBP6
Retinoblastoma binding protein 6
1.7341677
9.031465
TENC1
Tensin-like C1 domain containing phosphatase
1.7035551
9.118306
PAX6
Paired box 6
1.6825673
4.390296
NFAT5
Nuclear factor of activated T-cells 5 tonicity-responsive
1.6498569
5.38809
DGKG
Diacylglycerol kinase, gamma
1.6458238
9.031465
CFDP1
Craniofacial development protein 1
1.6289451
9.031465
VEZF1
Vascular endothelial zinc finger 1
1.6117046
9.118306
GAS1
Growth arrest-specific 1
1.5976216
9.118306
1.5447492
9.031465
ATPase H ? transporting lysosomal 9 kDa V0 subunit e1
1.5239171
9.118306
M33210 ATP6V0E1
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3.0509578 2.9806899
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Table 2 Molecular identification of MYBPC1 upstream and downstream phosphoprotein module in control and experiment Term
Control
Experiment
CREB5, MAPKAPK3
CREB5, ZC3HAV1, ROR1
Upstream Phosphoprotein Downstream Phosphoprotein
MAPKAPK3, CFDP1, PDCD4, RBBP6
control HIVE-control patients, experiment HIVE Table 3 Identification of only terms in control, only terms in experiment, both terms in control and experiment in MYBPC1 phosphoprotein cluster
Only terms in control
control HIVE-control patients, experiment HIVE
Only terms in experiment
Both terms in control and experiment
Signal transduction
Signal transduction
Transferase
Transferase
Post-translational protein modification
Post-translational protein modification
Developmental process
Developmental process
Glycoprotein
Glycoprotein Phosphoprotein
Fig. 1 MYBPC1 upstream and downstream phosphoprotein network construction in frontal cortex of HIVE-control patients by infer (a, c). MYBPC1 upstream and downstream phosphoprotein network constructions in frontal cortex of HIVE by infer (b, d). Arrowhead represents activation, empty cycle represents inhibition
integrative result reflected that CREB5, MAPKAPK3 inhibited MYBPC1, whereas in that of HIVE, CREB5, ZC3HAV1 activated MYBPC1, and ROR1 inhibited
MYBPC1. In MYBPC1 phosphoprotein module of downstream network of HIVE-control patients there was no result, whereas in that of HIVE, our integrative result
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Fig. 2 MYBPC1 upstream and downstream phosphoprotein module of frontal cortex of HIVE. Arrowhead represents activation, shield represents inhibition
illustrated that MYBPC1 activated MAPKAPK3 and inhibited CFDP1, PDCD4, RBBP6 (Figs. 1, 2). We found evidences from literatures to support our findings, such as MYBPC1, MAPKAPK3, CREB5 participate in phosphoprotein (de Sousa et al. 2007; Boettcher et al. 2007, 2008; Gerfen et al. 2008; Rajput et al. 2009; Scheggi et al. 2009; Collins and Borysenko 1984; Takizawa et al. 2002; Tan et al. 2001; Yuan et al. 2006). MAPKAPK3 had been proved to be concerned with molecular function of kinase, protein kinase and non-receptor serine/threonine protein kinase, and biological process of protein metabolism and modification, protein modification, protein phosphorylation, signal transduction, intracellular signaling cascade, MAPKKK cascade, immunity and defense, stress response (DAVID database). MAPKAPK3’s relational study also could be presented in these articles (Barber et al. 2008; Houben et al. 2005; Protopopov et al. 2002; Voncken et al. 2005; Zakowski et al. 2004). ROR1 was identified by molecular function of receptor, tyrosine protein kinase receptor, kinase, protein kinase, and protein kinase receptor, and by biological process of protein metabolism and modification, protein modification, protein phosphorylation, signal transduction, cell surface receptor-mediated signal transduction and receptor protein tyrosine kinase signaling pathway (DAVID database). ROR1’s relational study also could be presented in these articles (Baskar et al. 2008; Daneshmanesh et al. 2008; Fukuda et al. 2008;
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Shabani et al. 2007, 2008). CREB5’s molecular function consisted of transcription factor and nucleic acid binding, and it was involved in biological process of nucleoside, nucleotide and nucleic acid metabolism, mRNA transcription, mRNA transcription regulation, signal transduction, and intracellular signaling cascade (DAVID database). CREB5’s relational study also could be presented in these articles (Iijima-Ando et al. 2008; Jaworski et al. 2003; Sanchis-Segura et al. 2009; Warburton et al. 2005; Yang et al. 2004). ZC3HAV1 was relevant to molecular function of nucleic acid binding, and biological process of nucleoside, nucleotide, and nucleic acid metabolism (DAVID database). ZC3HAV1’s relational study also could be presented in these articles (Shim et al. 2008; Smolej et al. 2008; Tabaczewski et al. 2008; Wandroo et al. 2008; Zhu and Gao 2008). RBBP6’s molecular function contained nucleic acid binding and nuclease, and it was relevant to biological process of nucleoside, nucleotide and nucleic acid metabolism, premRNA processing and mRNA polyadenylation (DAVID database). RBBP6’s relational study also can be presented in these articles (Chibi et al. 2008; Pugh et al. 2006; Sakai et al. 1995). PDCD4 had been reported to be relevant to molecular function of nucleic acid binding, translation factor, translation elongation factor, and miscellaneous function, and it was involved in biological process of protein metabolism and modification, protein biosynthesis,
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apoptosis, induction of apoptosis (DAVID database). PDCD4’s relational study also could be presented in these articles (Lankat-Buttgereit et al. 2008; Schmid et al. 2008; Suzuki et al. 2008; Talotta et al. 2008; Wang et al. 2008a, b). We gained the positive result of MYBPC1 phosphoprotein module through the net numbers of activation minus inhibition compared with HIVE-control patients and predicted possibly the increase of MYBPC1 phosphoprotein module in HIVE. Importantly, we determined that MYBPC1 phosphoprotein cluster of HIVE was involved in signal transduction, transferase, post-translational protein modification, developmental process and glycoprotein (only in HIVE terms), the condition was vital to inflammation and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE included phosphoprotein, organelle, response to stimulus, nucleic acid binding, primary metabolic process, and biological regulation, and these terms were more relative to inflammation and cognition impairment, therefore, we deduced the stronger MYBPC1 phosphoprotein network in HIVE. It would be necessary of the stronger MYBPC1 phosphoprotein function to inflammation and cognition impairment of HIVE. In conclusion, we deduced the stronger MYBPC1 phosphoprotein module in HIVE. It would be necessary of the stronger MYBPC1 phosphoprotein function to inflammation and cognition impairment of HIVE. MYBPC1 computational phosphoprotein network construction and analysis of frontal cortex of HIVE was very useful to identify novel markers and potential targets for prognosis and therapy. MYBPC1 phosphoprotein interaction module construction in HIVE could be a new route for studying the pathogenesis of HIVE. Acknowledgments This study was supported by the National Natural Science Foundation in China (No. 60871100) and the Teaching and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry. State Key Lab of Pattern Recognition Open Foundation, Major science and technology projects of new transgenic biological breeds (2009ZX08012-001B), Key project of philosophical and social science of MOE (07JZD0005).
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