Journal of Molecular Neuroscience

, Volume 47, Issue 3, pp 649–658

Signal Transducer and Activator of Transcription 2 (STAT2) Metabolism Coupling Postmitotic Outgrowth to Visual and Sound Perception Network in Human Left Cerebrum by Biocomputation

Authors

    • Biomedical Center, School of Electronic EngineeringBeijing University of Posts and Telecommunications
  • Juxiang Huang
    • Biomedical Center, School of Electronic EngineeringBeijing University of Posts and Telecommunications
  • Minghu Jiang
    • Lab of Computational Linguistics, School of Humanities and Social SciencesTsinghua University
  • Hong Lin
    • Biomedical Center, School of Electronic EngineeringBeijing University of Posts and Telecommunications
Article

DOI: 10.1007/s12031-011-9702-4

Cite this article as:
Wang, L., Huang, J., Jiang, M. et al. J Mol Neurosci (2012) 47: 649. doi:10.1007/s12031-011-9702-4

Abstract

We constructed the high-expression signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum compared with low-expression (fold change ≥2) chimpanzee left cerebrum in GEO data set by using integration of gene regulatory network inference method with gene ontology (GO) analysis of STAT2-activated up- and downstream network. Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, etc. activated STAT2, and downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, etc. in human left cerebrum. STAT2-activated network enhanced regulation of small GTPase-mediated signal transduction, regulation of transcription, regulation of mitosis, regulation of cell growth, positive regulation of phosphoinositide 3-kinase cascade, positive regulation of fat cell differentiation, negative regulation of DNA replication, negative regulation of progression through cell cycle, cyclic nucleotide metabolism, lipid metabolism, carbohydrate metabolism, vitamin A metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism, fatty acid transport, intracellular protein transport, vesicle-mediated transport, lipid transport, retrograde transport, Ras protein signal transduction, Wnt receptor signaling pathway, nervous system development, cell extension, cell adhesion, cell differentiation, circadian rhythm, generation of precursor metabolites and energy, establishment of blood-nerve barrier, visual perception, sensory perception of sound, and poly-N-acetyllactosamine biosynthesis, as a result of inducing metabolism coupling postmitotic outgrowth to visual and sound perception in human left cerebrum.

Keywords

Signal transducer and activator of transcription 2 (STAT2)Human left cerebrumMetabolism coupling postmitotic outgrowth to visual and sound perception networkBiocomputation

Introduction

Signal transducer and activator of transcription 2 (STAT2) is our identified significant high-expression gene in human left cerebrum compared with low-expression (fold change ≥2) chimpanzee left cerebrum from GEO data set GDS2678 (http://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS2678). STAT2 is involved in nucleus, cytoplasm; transcription factor activity, signal transducer activity, hematopoietin/interferon class (D200-domain) cytokine receptor signal transducer activity, calcium ion binding, protein binding; regulation of transcription from RNA polymerase II promoter, signal transduction, JAK-STAT cascade, response to virus, interspecies interaction between organisms (GO database); Jak-STAT signaling pathway; adipogenesis, regulation of transcription from RNA polymerase II promoter, receptor signaling protein activity, signal transducer activity, EGFR1 NetPath 4; IFN alpha signaling pathway (KEGG, GenMAPP, BioCarta).

Visual and sound perceptions are relative to metabolism, transport, postmitotic outgrowth. Such as, glucose metabolism increases in visual pathways following habituation (Toga & Collins 1981); simultaneous measurement of metabolic and acoustic power and the efficiency of sound production: relatively low average metabolic rate, acoustic power on average greater, the efficiency of sound production significantly higher (Prestwich & O'Sullivan 2005); transport, metabolism, and the role of vitamin A in the vision process and metabolism of vitamin A in the visual cycle (Nowak & Nawrocki 1985); insulin pathway mutants affect visual physiology and brain function besides growth, lipid, and carbohydrate metabolism in drosophila (Murillo-Maldonado et al. 2011); signal transduction in the visual cascade involves specific lipid-protein interactions: signaling proteins group-specific and state-dependent interaction with the phospholipids of the photoreceptor membrane (Hessel et al. 2003); nervous activity and RNA metabolism in the visual cortex of rat brain (Dewar & Reading 1970); cerebral blood flow, blood volume, and oxygen metabolism dynamics in human visual and motor cortex: the blood-oxygenation-level-dependent signal, can reflect composite changes in the cerebral metabolic rate of oxygen consumption, become more negative (P = 0.003) and persisted longer (P = 0.006) in the visual cortex compared with the motor cortex (Donahue et al. 2009); the visual pathway structures are metabolically affected in a different manner by aging, the ability of the retina and superior colliculus to metabolize lipids to be age invariant (Alberghina & Viola 1989); arthropod photoreceptors use histamine as a neurotransmitter, photoreceptor synapses requires histamine inactivation and metabolism (Battelle & Hart 2002); lipid metabolism occur in the Parkinson’s disease visual cortex in the absence of obvious pathology, normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms (Cheng et al. 2011); visual cortex plasticity by monocular deprivation during the critical period increased levels of kinases and proteins regulating the actin-cytoskeleton and endocytosis (Dahlhaus et al. 2011); 5-HT(1A) receptor and BDNF-trkB signalling in driving a transitory epigenetic remodelling of chromatin structure that underlies the reactivation of plasticity in the visual system (Maya Vetencourt et al. 2011); mitochondrial dysfunction due to Leber’s hereditary optic neuropathy as a cause of visual loss (Niehusmann et al. 2011); in rat visual cortical neurons, AMP-activated protein kinase mediates activity-dependent regulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha and nuclear respiratory factor 1 expression (Yu & Yang 2011); the activation of ERK1/2 and p38 mitogen-activated protein kinases is dynamically regulated in the developing rat visual system (Oliveira et al. 2008); inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals (Wang et al. 2007). And also, different molecular concentrations are responsible for different functions, the same molecule together with the different molecules will have different functions. The mechanisms that shut off a signal are as important as the mechanisms that turn it on. Yet the distinct high-expression STAT2 metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum remains to be elucidated.

The origin of human was accompanied by the emergence of new behavioral and cognitive functions, such as language and specialized forms of abstract representation. Human language usually localized predominantly in the left hemisphere of left cerebrum. Cognitive studies also proved that the left hemisphere was dominant for mathematical and logical reasoning (Sun & Walsh 2006). Human and chimpanzee differed considerably in mental and linguistic capabilities, despite only approximately 1% difference in genomic DNA sequence (Gu & Gu 2003). Microscopic study proved that structure in the human left cerebrum was organized differently than those of chimpanzees (Buxhoeveden & Casanova 2002; Preuss & Coleman 2002). Therefore, the considerable intelligent differences could be explained by the distinctions between chimpanzee and human left cerebrum evolution. Some researchers compared gene expression profiles for the cerebral cortex of humans and chimpanzees displaying a distinctive pattern of gene expression of human left cerebrum relative to non-human primates (Caceres et al. 2003). The results indicated that many function-gene expression changes in the human cortex involved predominantly increased expression, and that many of the genes up-regulated in humans could be related to higher levels of neuronal activity (Caceres et al. 2003). Here we constructed the high-expression STAT2-activated network in human left cerebrum from GEO data set by gene regulatory network inference method based on linear programming and decomposition procedure.

In this study, we have established STAT2-activated network. We have put forwards hypothesis of STAT2 metabolism coupling postmitotic outgrowth to visual and sound perception network and verified through GO analysis of STAT2 common activated up- and downstream, only up- or downstream network and also each other in human left cerebrum.

Materials and Methods

We used microarrays containing 12,558 genes from 15 chimpanzee and 14 human left cerebrum samples in GEO data set GDS2678 (http://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS2678). We chose 15 chimpanzee and 14 human left cerebrum samples from several cortical brain regions containing brain cerebellum from the left hemisphere, anterior cingulated, anterior inferior parietal, anterior inferior temporal, middle frontal gyrus, frontal pole, etc. in GEO dataset GDS2678. The raw microarray data were preprocessed by log base 2 because GDS2678 was not transformed by log base 2.

Significant expressed genes were identified using significant analysis of microarrays (SAM) (http://wwwstat.stanford.edu/~tibs/SAM/) (Storey 2002). We normalized data by log2, selected two classes unpaired and minimum fold change ≥2 and chose the significant highly expressed value genes of human left cerebrum compared with that of chimpanzee left cerebrum under the false-discovery rate and q value were 0%. The q value is like the well-known P value, but adapted to multiple-testing situations.

To verify whether our identified genes could separate two samples groups chimpanzee versus human left cerebrum, we did average linkage of hierarchical clustering by cluster 3.0 (http://bonsai.ims.tokyo.ac.jp/~mdehoon/software/cluster) (Wang et al. 2011).

STAT2-activated network of human left cerebrum was constructed based on GRNInfer and GVedit tools (http://www.graphviz.org/About.php). GRNInfer is a novel mathematic method called GNR (Gene Network Reconstruction tool) based on linear programming and a decomposition procedure for inferring gene networks (Wang et al. 2006). We established STAT2-activated network of human left cerebrum based on the fold change ≥2 distinguished genes and selected parameters as lambda 0.0 because we used one data set. 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 the different edge density. The threshold parameters make the edge whose strength of link is smaller than threshold not shown in the network graph. The smaller this parameter, the more edges in the network graph. We selected threshold 1.0e−8.

STAT2-activated network of human left cerebrum was analyzed using Molecule Annotation System, MAS (CapitalBio Corporation, Beijing, China; http://bioinfo.capitalbio.com/mas3/). MAS is a Web-based software toolkit for a whole data mining and function annotation solution to extract and analyze biological molecules relationships from public databases. The primary databases of MAS integrated various well-known biological resources, such as Gene Ontology (http://www.geneontology.org), KEGG (http://www.genome.jp/kegg/), BioCarta (http://www.biocarta.com/), GenMapp (http://www.genmapp.org/), HPRD (http://www.hprd.org/), MINT (http://mint.bio.uniroma2.it/mint/Welcome.do), BIND (http://www.blueprint.org/), Intact (http://www.ebi.ac.uk/intact/), UniGene (www.ncbi.nlm.nih.gov/UniGen), OMIM (http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?db=OMIM), and disease (http://bioinfo.capitalbio.com/mas3/). MAS offers various query entries and graphics result. The algorithm is P, q value in GO and pathway of module seen in reference (Sun et al. 2011).

Results

First, we established total network of 441 significant high expression molecules (fold change ≥2) from 12,558 genes of 14 human left cerebrums compared with 15 chimpanzee left cerebrums by GRNInfer. Second, we identified high-expression STAT2 network from our total constructed network in human left cerebrum. Third, we identified STAT2 up- and downstream network in human left cerebrum. Fourth, we further identified activated molecules from STAT2 up- and downstream network in human left cerebrum.

Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, PCDHGA8, PPARD, EIF1AY, UNG, CTRL, ACOX3 activated STAT2, and the downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, GATAD1, GEM, BAG5, SPAG9, B3GNT1, SERINC3, FBXL5, GOLGA3, SMA4, BMP2K, DDX3Y, EXTL2, BTRC, CYFIP2, RFK, RCC1, MED6, INHBB, CHAD, MAF, THBS2, LIMCH1 in human left cerebrum, as shown in Figs. 1 and 2.
https://static-content.springer.com/image/art%3A10.1007%2Fs12031-011-9702-4/MediaObjects/12031_2011_9702_Fig1_HTML.gif
Fig. 1

STAT2 upstream-activated network in human left cerebrum by GRNInfer. Arrowhead represents activation relationship

https://static-content.springer.com/image/art%3A10.1007%2Fs12031-011-9702-4/MediaObjects/12031_2011_9702_Fig2_HTML.gif
Fig. 2

STAT2 downstream-activated network in human left cerebrum by GRNInfer. Arrowhead represents activation relationship

We first identified GO terms of total 441 significant expression molecules and further extracted GO terms of STAT2-activated up- and downstream network in human left cerebrum, respectively, as shown in Tables 1 and 2.
Table 1

GO analysis of STAT2 upstream-activated network in human left cerebrum

STAT2 upstream-activated network

Cellular component

Molecular function

Biological process

RECQL

nucleus

nucleotide binding, DNA binding, ATP-dependent DNA helicase activity, protein binding, ATP binding, hydrolase activity

DNA repair, DNA recombination

PDIA2

endoplasmic reticulum, endoplasmic reticulum lumen

protein disulfide isomerase activity, protein binding, isomerase activity

response to hypoxia, protein folding, protein retention in ER, cell redox homeostasis

ENOSF1

mitochondrion

magnesium ion binding, isomerase activity

metabolism, amino acid catabolism

THBS4

extracellular region, extracellular matrix (sensu Metazoa), platelet alpha granule

structural molecule activity, calcium ion binding, protein binding, heparin binding

substrate-bound cell migration, cell extension, cell adhesion

RASGRP1

Golgi membrane, intracellular, membrane fraction, cytoplasm, endoplasmic reticulum, endoplasmic reticulum membrane, Golgi apparatus, plasma membrane

guanyl-nucleotide exchange factor activity, calcium ion binding, protein binding, zinc ion binding, diacylglycerol binding

Ras protein signal transduction, cell differentiation, regulation of small GTPase-mediated signal transduction

PER2

nucleus, cytoplasm

signal transducer activity, protein binding

transcription, regulation of transcription, DNA-dependent, signal transduction, circadian rhythm

PDE8A

cellular component, cytoplasm, Golgi apparatus, plasma membrane

two-component response regulator activity, magnesium ion binding, 3′,5′-cyclic-nucleotide phosphodiesterase activity, hydrolase activity, manganese ion

two-component signal transduction system (phosphorelay), cAMP catabolism, regulation of transcription, DNA dependent, cyclic nucleotide metabolism

ORC2L

origin recognition complex, nucleus, nucleoplasm

DNA replication origin binding, protein binding

negative regulation of transcription from RNA polymerase II promoter, DNA replication, DNA replication initiation

DCI

mitochondrion, mitochondrial inner membrane, mitochondrial matrix

dodecenoyl-CoA delta-isomerase activity, isomerase activity

lipid metabolism, fatty acid metabolism, fatty acid betaoxidation, metabolism

OGG1

nucleus, nucleoplasm, mitochondrion

damaged DNA binding, endonuclease activity, protein binding, oxidized purine base lesion DNA N-glycosylase activity, hydrolase activity, acting on glycosyl bonds, lyase activity

base-excision repair, nucleotide-excision repair, response to DNA damage stimulus, metabolism, depurination

SMA4

nucleus, nucleoplasm, spliceosome complex, cytoplasm, cytosol, Cajal body

RNA binding, protein binding

spliceosome assembly, spliceosomal snRNP biogenesis, mRNA processing, RNA splicing

GPD1

soluble fraction, cytoplasm, cytosol, glycerol-3-phosphate dehydrogenase complex

glycerol-3-phosphate dehydrogenase (NAD+) activity, glycerol-3-phosphate dehydrogenase activity, binding, protein homodimerization activity, NAD binding

carbohydrate metabolism, gluconeogenesis, glycerol-3-phosphate catabolism, oxidation reduction

PCDHGA8

plasma membrane, integral to membrane

calcium ion binding, protein binding

cell adhesion, homophilic cell adhesion

PPARD

nucleus

transcription factor activity, steroid hormone receptor activity, fatty acid binding, drug binding, zinc ion binding, transcriptional repressor activity, sequence-specific DNA binding, metal ion binding, NF-kappaB binding

negative regulation of transcription from RNA polymerase II promoter, glucose metabolism, generation of precursor metabolites and energy, transcription, lipid metabolism, fatty acid beta-oxidation, vitamin A metabolism, apoptosis, embryo implantation, cholesterol metabolism, axon ensheathment, epidermis development, positive regulation of phosphoinositide 3-kinase cascade, glucose transport, fatty acid transport, cell differentiation, cell-substrate adhesion, wound healing, anagen, keratinocyte proliferation, positive regulation of fat cell differentiation, decidualization, keratinocyte migration

EIF1AY

cytoplasm

RNA binding, translation initiation factor activity, protein binding

translational initiation

UNG

nucleus, mitochondrion

uracil DNA N-glycosylase activity, protein binding, hydrolase activity, acting on glycosyl bonds

base-excision repair, response to DNA damage stimulus, metabolism, interspecies interaction between organisms

CTRL

extracellular space

serine-type endopeptidase activity, peptidase activity

proteolysis, digestion

ACOX3

peroxisome

acyl-CoA dehydrogenase activity, acyl-CoA oxidase activity, electron carrier activity, FAD binding

lipid metabolism, fatty acid metabolism, fatty acid betaoxidation, bile acid metabolism, oxidation reduction

Table 2

GO analysis of STAT2 downstream-activated network in human left cerebrum

STAT2 downstream-activated network

Cellular component

Molecular function

Biological process

GSTM3

cytoplasm

glutathione transferase activity, protein binding, transferase activity

establishment of blood-nerve barrier, metabolism, response to estrogen stimulus

GOSR1

Golgi membrane, Golgi apparatus, membrane, integral to membrane, SNARE complex

SNAP receptor activity

intracellular protein transport, ER to Golgi vesicle-mediated transport, intra-Golgi vesicle-mediated transport, vesicle-mediated transport, retrograde transport, endosome to Golgi

SH3BGR

cytosol

SH3/SH2 adaptor activity, SH3 domain binding

protein complex assembly

SH3BGR

nucleus, cytoplasm

SH3/SH2 adaptor activity, SH3 domain binding

 

OSBPL8

nucleus, nucleolus, cytoplasm

 

lipid transport, steroid metabolism

PHYH

peroxisome

iron ion binding, protein binding, electron carrier activity, oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen, Lascorbic acid binding, metal ion binding, phytanoyl-CoA dioxygenase activity

lipid metabolism, nervous system development, visual perception, sensory perception of sound, response to stimulus, oxidation reduction

SAPS2

cytoplasm

protein binding

 

C21orf33

mitochondrion

  

PDIA2

endoplasmic reticulum, endoplasmic reticulum lumen

protein disulfide isomerase activity, protein binding, isomerase activity

response to hypoxia, protein folding, protein retention in ER, cell redox homeostasis

TRAPPC6A

endoplasmic reticulum, Golgi apparatus

 

vesicle-mediated transport

ENOSF1

mitochondrion

magnesium ion binding, isomerase

metabolism, amino acid catabolism

CAMTA1

nucleus, cytoplasm

 

transcription, regulation of transcription,

DNA-dependent

GTF2I

nucleus, cytoplasm

transcription factor activity, protein binding, general RNA polymerase II transcription factor activity

transcription, regulation of transcription, DNA-dependent, transcription initiation from RNA polymerase II promoter, signal transduction

GATAD1

nucleus

transcription factor activity, zinc ion binding, sequence-specific DNA binding, metal ion binding

regulation of transcription, DNA-dependent

GEM

plasma membrane

nucleotide binding, calmodulin binding, GTP binding

immune response, cell surface receptor linked signal transduction, small GTPase-mediated signal transduction

GEM

nucleoplasm

protein binding

negative regulation of DNA replication, negative regulation of progression through cell cycle

BAG5

 

protein binding

protein folding, apoptosis

SPAG9

acrosome, cytoplasm, integral to membrane

protein binding

spermatogenesis

B3GNT1

Golgi membrane, Golgi apparatus, membrane, integral to membrane

galactosyltransferase activity, UDPgalactose: beta-N-acetylglucosamine beta-1,3-galactosyltransferase activity, transferase activity, transferring glycosyl groups, manganese ion binding

protein amino acid glycosylation

B3GNT1

Golgi membrane, Golgi apparatus, membrane, integral to membrane, integral to Golgi membrane

N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase activity, transferase activity, transferring glycosyl groups

poly-N-acetyllactosamine biosynthesis

SERINC3

Golgi apparatus, plasma membrane, integral to membrane

protein binding

induction of apoptosis

FBXL5

ubiquitin ligase complex

ubiquitin-protein ligase activity, protein binding

protein ubiquitination, modification-dependent protein catabolism

GOLGA3

Golgi membrane, cytoplasm, Golgi apparatus, membrane, Golgi transport complex

transporter activity, protein binding

intra-Golgi vesicle-mediated transport

SMA4

nucleus, nucleoplasm, spliceosome complex, cytoplasm, cytosol, Cajal body

RNA binding, protein binding

spliceosome assembly, spliceosomal snRNP biogenesis, mRNA processing, RNA splicing

BMP2K

nucleus

nucleotide binding, protein serine/threonine kinase activity, ATP binding, transferase activity

protein amino acid phosphorylation

DDX3Y

nucleus, cytoplasm, plasma membrane

nucleotide binding, DNA binding, RNA binding, helicase activity, ATP binding, ATP-dependent helicase activity, hydrolase activity

 

EXTL2

extracellular region, endoplasmic reticulum, membrane, integral to membrane, intrinsic to endoplasmic reticulum membrane

glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity, transferase activity, transferring hexosyl groups, manganese ion binding, alpha-1,4-N-acetylgalactosaminyltransferase activity,

N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism

BTRC

cytoplasm, cytosol

protein binding, ligase activity

ubiquitin-dependent protein catabolism, signal transduction, Wnt receptor signaling pathway, interspecies interaction between organisms, positive regulation of ubiquitin ligase activity during mitotic cell cycle

CYFIP2

cytoplasm, synaptosome, cell junction, synapse, perinuclear

protein binding

apoptosis, cell–cell adhesion

RFK

cytoplasm, cytosol

nucleotide binding, magnesium ion binding, ATP binding, zinc ion binding, riboflavin kinase activity, transferase

riboflavin biosynthesis

RCC1

nuclear chromatin, condensed nuclear chromosome, nucleus, cytoplasm

chromatin binding, guanyl-nucleotide exchange factor activity, Ran guanylnucleotide exchange factor activity, histone binding

G1/S transition of mitotic cell cycle, cell cycle, mitotic spindle organization and biogenesis, regulation of mitosis, regulation of S phase of mitotic cell cycle, cell division

MED6

mediator complex, nucleus

RNA polymerase II transcription factor activity, transcription coactivator activity

positive regulation of transcription from RNA polymerase II promoter

INHBB

extracellular region

cytokine activity, hormone activity, growth factor activity, protein homodimerization activity, host cell surface receptor binding

ovarian follicle development, defense response, response to external stimulus, cell differentiation, growth, positive regulation of follicle-stimulating hormone secretion, negative regulation of follicle-stimulating hormone secretion, negative regulation of hepatocyte growth factor biosynthesis

CHAD

extracellular region, extracellular matrix (sensu Metazoa)

extracellular matrix structural constituent, protein binding

regulation of cell growth

MAF

chromatin, nucleus

transcription factor activity, RNA polymerase II transcription factor activity, sequence-specific DNA binding

regulation of transcription, DNAdependent, transcription from RNA polymerase II promoter, negative regulation of progression through cell cycle

THBS2

extracellular region, platelet alpha granule lumen

structural molecule activity, calcium ion binding, protein binding, heparin binding

cell adhesion

LIMCH1

 

actin binding, zinc ion binding, metal ion binding

actomyosin structure organization and biogenesis

Discussion

Our aim is to construct, interpret and verify novel high-expression STAT2 metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum. We have already constructed some novel molecular networks from different databases and analyzed significance of our work presented in our articles (Huang et al. 2010a, b; Sun et al. 2008, 2010; Wang et al. 2009a, b, 2010a, b). Such as, we inferred BIRC5 cell cycle module more mitosis but less complex-dependent proteasomal ubiquitin-dependent protein catabolism, as a result of increasing cell division and cell numbers in no-tumor hepatitis/cirrhotic tissues; more protein amino acid autophosphorylation but less negative regulation of ubiquitin ligase activity during mitotic cell cycle, as a result of increasing growth and cell volume in HCC (Wang et al. 2011). In this study, we have established STAT2-activated network. We have put forward the hypothesis of STAT2 metabolism coupling postmitotic outgrowth to visual and sound perception network and verified through GO analysis of STAT2 common activated up- and downstream, only up- or downstream network and also each other in human left cerebrum.

We first verified that our identified genes could separate two samples groups chimpanzee versus human left cerebrum by cluster 3.0 (Wang et al. 2011).

Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, PCDHGA8, PPARD, EIF1AY, UNG, CTRL, ACOX3 activated STAT2, and the downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, GATAD1, GEM, BAG5, SPAG9, B3GNT1, SERINC3, FBXL5, GOLGA3, SMA4, BMP2K, DDX3Y, EXTL2, BTRC, CYFIP2, RFK, RCC1, MED6, INHBB, CHAD, MAF, THBS2, LIMCH1 in human left cerebrum (Fig. 1 and 2). We identified cellular component, molecular function, biological process of high-expression STAT2-activated network in human left cerebrum by GO database (Table 1 and 2).

STAT2 upstream-activated regulation subnetwork enhanced regulation of small GTPase-mediated signal transduction, transcription; Downstream increased regulation of transcription, mitosis, S phase of mitotic cell cycle, cell growth, transcription from RNA polymerase II promoter in human left cerebrum.

STAT2 upstream-activated positive regulation subnetwork enhanced positive regulation of phosphoinositide 3-kinase cascade, fat cell differentiation; Downstream heightened positive regulation of ubiquitin ligase activity during mitotic cell cycle, transcription from RNA polymerase II promoter in human left cerebrum.

STAT2 upstream-activated negative regulation subnetwork enhanced negative regulation of transcription from RNA polymerase II promoter; Downstream increased negative regulation of DNA replication, progression through cell cycle in human left cerebrum.

STAT2 upstream-activated metabolism subnetwork heightened metabolism, cyclic nucleotide metabolism, lipid metabolism, fatty acid metabolism, carbohydrate metabolism, glucose metabolism, vitamin A metabolism, cholesterol metabolism, bile acid metabolism; Downstream enhanced metabolism, steroid metabolism, lipid metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism in human left cerebrum.

STAT2 upstream-activated transport subnetwork increased glucose transport, fatty acid transport; Downstream enhanced intracellular protein transport, ER to Golgi vesicle-mediated transport, intra-Golgi vesicle-mediated transport, vesicle-mediated transport, retrograde transport, lipid transport in human left cerebrum.

STAT2 upstream-activated signal transduction subnetwork enhanced Ras protein signal transduction, signal transduction, two-component signal transduction system (phosphorelay); Downstream increased signal transduction, cell surface receptor linked signal transduction, small GTPase-mediated signal transduction, Wnt receptor signaling pathway in human left cerebrum.

STAT2 upstream-activated response subnetwork heightened response to hypoxia, response to DNA damage stimulus; Downstream increased response to estrogen stimulus, response to stimulus, response to hypoxia, immune response, defense response, response to external stimulus, response to virus in human left cerebrum.

STAT2 upstream-activated transcription subnetwork heightened transcription; Downstream increased transcription, transcription initiation from RNA polymerase II promoter, transcription from RNA polymerase II promoter in human left cerebrum.

And also, STAT2 upstream-activated other subnetwork heightened DNA repair, DNA recombination, protein folding, protein retention in ER, cell redox homeostasis, amino acid catabolism, substrate-bound cell migration, cell extension, cell adhesion, cell differentiation, circadian rhythm, cAMP catabolism, DNA replication, DNA replication initiation, fatty acid beta-oxidation, base-excision repair, nucleotide-excision repair, depurination, spliceosome assembly, spliceosomal snRNP biogenesis, mRNA processing, RNA splicing, gluconeogenesis, glycerol-3-phosphate catabolism, oxidation reduction, homophilic cell adhesion, generation of precursor metabolites and energy, apoptosis, embryo implantation, axon ensheathment, cell-substrate adhesion, wound healing, anagen, keratinocyte proliferation, keratinocyte migration, translational initiation, interspecies interaction between organisms, proteolysis, digestion, epidermis development; Downstream increased establishment of blood-nerve barrier, endosome to Golgi, protein complex assembly, visual perception, sensory perception of sound, oxidation reduction, protein folding, protein retention in ER, cell redox homeostasis, amino acid catabolism, apoptosis, protein amino acid glycosylation, poly-N-acetyllactosamine biosynthesis, induction of apoptosis, protein ubiquitination, modification-dependent protein catabolism, spliceosome assembly, spliceosomal snRNP biogenesis, mRNA processing, RNA splicing, protein amino acid phosphorylation, ubiquitin-dependent protein catabolism, interspecies interaction between organisms, cell-cell adhesion, riboflavin biosynthesis, G1/S transition of mitotic cell cycle, cell cycle, mitotic spindle organization and biogenesis, cell division, cell differentiation, growth, JAK-STAT cascade, cell adhesion, actomyosin structure organization and biogenesis, nervous system development in human left cerebrum.

Therefore, we proposed and verified STAT2-activated network induced metabolism coupling postmitotic outgrowth to visual and sound perception, it is consistent with high-expression STAT2-activated up- and downstream network in human left cerebrum.

In summary, we constructed the high-expression STAT2 metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum compared with low-expression (fold change ≥2) chimpanzee left cerebrum in GEO data set, by using integration of gene regulatory network inference method with GO analysis of STAT2-activated up- and downstream network. Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, etc. activated STAT2, and downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, etc. in human left cerebrum. STAT2-activated network enhanced regulation of small GTPase-mediated signal transduction, regulation of transcription, regulation of mitosis, regulation of cell growth, positive regulation of phosphoinositide 3-kinase cascade, positive regulation of fat cell differentiation, negative regulation of DNA replication, negative regulation of progression through cell cycle, cyclic nucleotide metabolism, lipid metabolism, carbohydrate metabolism, vitamin A metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism, fatty acid transport, intracellular protein transport, vesicle-mediated transport, lipid transport, retrograde transport, Ras protein signal transduction, Wnt receptor signaling pathway, nervous system development, cell extension, cell adhesion, cell differentiation, circadian rhythm, generation of precursor metabolites and energy, establishment of blood-nerve barrier, visual perception, sensory perception of sound, and poly-N-acetyllactosamine biosynthesis, as a result of inducing metabolism coupling postmitotic outgrowth to visual and sound perception in human left cerebrum.

Acknowledgments

This work was supported by the National Natural Science Foundation in China (No. 60871100) and (No. 61171114), the Returned Overseas Chinese Scholars for Scientific research Foundation of State Education Ministry, Significant Science and Technology Project for New Transgenic Biological Species (2009ZX08012-001B), Automatical Scientific Planning of Tsinghua University (20111081023 and 20111081010), State Key Lab of Pattern Recognition Open Foundation.

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