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n3:pmcid
PMC0
bibo:doi
10.1038%2Fnature08712
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methods
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between gene expression and DNA copy number for the MGES genes was determined using data from 76 high-grade gliomas for which both gene expression array and array comparative genomic hybridization (aCGH) profiling were performed>>4<<. Tumors were grouped based on molecular subtype (mesenchymal, proneural, or proliferative) and the mean expression for MGES genes were determined in each group.
n3:mentions
n2:16530701
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_:vb6691553
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The normalized copy number of each gene was interpolated based on the copy number of the nearest genomic clone on the CGH array as determined by comparison of the sequence annotation of both array platforms, as previously described>>21<<.
n3:mentions
n2:15753362
Subject Item
_:vb6691554
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Expression profiles used in the analysis were previously characterized using Affymetrix HU-133A microarrays and preprocessed by MAS 5.0 normalization procedure>>4<<. First, candidate interactions between a TF (x) and its potential target (y) are identified by computing pairwise mutual information, MI[x; y], using a Gaussian kernel estimator12 and by thresholding the mutual information based on the
n3:mentions
n2:16530701
Subject Item
_:vb6691555
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First, candidate interactions between a TF (x) and its potential target (y) are identified by computing pairwise mutual information, MI[x; y], using a Gaussian kernel estimator>>12<< and by thresholding the mutual information based on the null-hypothesis of statistical independence (p < 0.05 Bonferroni corrected for the number of tested pairs).
n3:mentions
n2:17406294
Subject Item
_:vb6691556
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rdf:value
each MGES gene was computed as follows: the log2 expression of the i-th MGES gene was considered as the response variable and the log2-expression of the TFs as the explanatory variables in the linear model log xi = ∑ αij log fj + βij >>44<<. Here, fj represents the expression of the j-th TF in the model and the (αij, βij) are linear coupling coefficients computed by standard regression analysis.
n3:mentions
n2:12730377
Subject Item
_:vb6691557
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n3:Context
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The log-transformation allows convenient linear representation of multiplicative interactions between TF activities>>44<<, 45. TFs were individually added to the model, each time selecting the one contributing the most significant reduction in relative expression error (predicted vs. observed), until error-reduction was no longer significant.
n3:mentions
n2:12730377
Subject Item
_:vb6691558
rdf:type
n3:Context
rdf:value
The log-transformation allows convenient linear representation of multiplicative interactions between TF activities44, >>45<<. TFs were individually added to the model, each time selecting the one contributing the most significant reduction in relative expression error (predicted vs. observed), until error-reduction was no longer significant.
n3:mentions
n2:11175784
Subject Item
_:vb6691559
rdf:type
n3:Context
rdf:value
Primary mNSCs were isolated from E13.5 mouse telencephalon and cultured in the presence of FGF-2 and EGF (20 ng/ml each) as described>>42<<. Differentiation of NSCs was induced by culturing neurospheres on laminin-coated dishes in NSC medium in the absence of growth factors. mNSC expressing Stat3C and C/EBPβ, were generated by retroviral infections using supernatant from
n3:mentions
n2:12086863
Subject Item
_:vb6691560
rdf:type
n3:Context
rdf:value
ChIP was performed as described in Ref.>>47<<. SNB75 cell lysates were precleared with Protein A/G beads (Santa Cruz) and incubated at 4°C overnight with 1 µg of polyclonal antibody specific for C/EBPβ (sc-150, Santa Cruz), Stat3 (sc-482, Santa Cruz), FosL2 (Fra2, sc-604, Santa
n3:mentions
n2:11511539
Subject Item
_:vb6691561
rdf:type
n3:Context
rdf:value
QRT-PCR results were analyzed by the ΔΔCT method>>48<< using 18S as housekeeping gene.
n3:mentions
n2:11846609
Subject Item
_:vb6691562
rdf:type
n3:Context
rdf:value
Hybridization data was obtained with an iScan BeadArray scanner (Illumina) and pre-processed by variance stabilization and robust spline normalization implemented in the lumi package under the R-system>>49<<. Gene expression data have been deposited in GEO with the following accession numbers: GSE19113 for mouse and GSE19114 for human data.
n3:mentions
n2:18467348
Subject Item
_:vb6691563
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Immunofluorescence staining was performed as previously described>>50<<. Primary antibodies and dilutions were: SMA (mouse monoclonal, Sigma, 1:200), Fibronectin (mouse monoclonal, BD Biosciences, 1:
n3:mentions
n2:16705184
Subject Item
_:vb6691564
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Immunostaining was performed as previously described>>51<<. Primary antibodies and dilutions:
n3:mentions
n2:18488021
Subject Item
_:vb6691565
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n3:Context
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Immunohistochemistry of primary human GBM was performed as previously described>>52<<. The primary antibodies and dilutions were: anti-YKL40 (rabbit polyclonal, Quidel, 1:750), anti C/EBPβ, (rabbit polyclonal, Santa Cruz, 1:250) and anti-p-Stat3 (rabbit monoclonal, Cell Signaling, 1;25), Scoring for YKL40 was based on a
n3:mentions
n2:11221842
Subject Item
_:vb6691566
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G vectors into human embryonic kidney 293T cells using Fugene 6 (Roche). Lentiviral infections were performed as described>>51<<.
n3:mentions
n2:18488021
Subject Item
_:vb6691567
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n5:Section
dc:title
discussion
n5:contains
_:vb6691568 _:vb6691569 _:vb6691570 _:vb6691571 _:vb6691572 _:vb6691573
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_:vb6691568
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Recently, there have been several unsuccessful attempts to identify common expression signatures predictive of the same cellular phenotype>>33<<. Our approach produced virtually identical regulatory MR modules when applied to two completely distinct datasets and signatures associated with poor-prognosis in HGGs, thus indicating that MRs of mammalian phenotype signatures may be
n3:mentions
n2:15308542
Subject Item
_:vb6691569
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n3:Context
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Other methods, including differential expression analysis, DNA-binding-site enrichment analysis>>8<< and relevance network analysis34 could not identify C/EBPβ and Stat3 as MRs (see Supplementary Note 2).
n3:mentions
n2:15920528
Subject Item
_:vb6691570
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Other methods, including differential expression analysis, DNA-binding-site enrichment analysis8 and relevance network analysis>>34<< could not identify C/EBPβ and Stat3 as MRs (see Supplementary Note 2).
n3:mentions
n2:10902190
Subject Item
_:vb6691571
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Interestingly, C/EBPβ and Stat3 are expressed in the developing nervous system>>35<<–38. However, while Stat3 induces astrocyte differentiation and inhibits neuronal differentiation of neural stem/progenitor cells, C/EBPβ promotes neurogenesis and opposes gliogenesis39–41. How can the combined activity of C/EBPβ and Stat3
n3:mentions
n2:9334309 n2:16242406 n2:9603207 n2:15936952
Subject Item
_:vb6691572
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However, while Stat3 induces astrocyte differentiation and inhibits neuronal differentiation of neural stem/progenitor cells, C/EBPβ promotes neurogenesis and opposes gliogenesis>>39<<–41. How can the combined activity of C/EBPβ and Stat3 reprogram NSCs toward an aberrant lineage (mesenchymal) and oppose the genesis of the normal neural lineages (neuronal and glial)? We propose that mesenchymal transformation results
n3:mentions
n2:12441050 n2:10205054 n2:16291948
Subject Item
_:vb6691573
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cells whereas it operates to permanently drive the aberrant mesenchymal phenotype in the context of the genetic and epigenetic changes that accompany high-grade gliomagenesis (EGFR amplification, PTEN loss, Akt activation, etc.)>>4<<. Since expression of C/EBPβ and Stat3 in human glioma is essential to maintain the tumor initiating capacity and the ability to invade the normal brain, the two TFs provide important clues for diagnostic and pharmacological intervention.
n3:mentions
n2:16530701
Subject Item
_:vb6691574
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n5:Section
dc:title
methods summary
n5:contains
_:vb6691576 _:vb6691577 _:vb6691575
Subject Item
_:vb6691575
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Primary NSCs were isolated from E13.5 mouse telencephalon and cultured in the presence of FGF-2 and EGF as described>>42<<. Differentiation was induced by culturing NSCs in NSC medium without EGF and FGF-2.
n3:mentions
n2:12086863
Subject Item
_:vb6691576
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n3:Context
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GBM transcriptional network was generated by ARACNe>>12<<. Total RNA was reverse transcribed to complementary DNA and amplified using primers specific for human and murine transcripts.
n3:mentions
n2:17406294
Subject Item
_:vb6691577
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The statistical significance of the enrichment of a ranked list of genes in a smaller set of genes was determined as described>>43<<.
n3:mentions
n2:16199517
Subject Item
_:vb6691578
rdf:type
n5:Section
dc:title
a transcriptional module is linked to the mges of hggs
n5:contains
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We thus used the ARACNe algorithm>>9<< to assemble a genome-wide repertoire of HGGs-specific transcriptional interactions (the HGG-interactome) from 176 gene expression profiles of grade III (anaplastic astrocytoma) and grade IV (GBM) samples previously classified into three
n3:mentions
n2:15778709
Subject Item
_:vb6691580
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n3:Context
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from 176 gene expression profiles of grade III (anaplastic astrocytoma) and grade IV (GBM) samples previously classified into three molecular signature groups – proneural, proliferative, and mesenchymal (Supplementary Table 1a–c)>>4<<, 20, 21. ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, 16, further refined to infer directed (i.e. causal) interactions12, 22 (see Methods).
n3:mentions
n2:16530701
Subject Item
_:vb6691581
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n3:Context
rdf:value
from 176 gene expression profiles of grade III (anaplastic astrocytoma) and grade IV (GBM) samples previously classified into three molecular signature groups – proneural, proliferative, and mesenchymal (Supplementary Table 1a–c)4, >>20<<, 21. ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, 16, further refined to infer directed (i.e. causal) interactions12, 22 (see Methods).
n3:mentions
n2:15374961
Subject Item
_:vb6691582
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from 176 gene expression profiles of grade III (anaplastic astrocytoma) and grade IV (GBM) samples previously classified into three molecular signature groups – proneural, proliferative, and mesenchymal (Supplementary Table 1a–c)4, 20, >>21<<. ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, 16, further refined to infer directed (i.e. causal) interactions12, 22 (see Methods).
n3:mentions
n2:15753362
Subject Item
_:vb6691583
rdf:type
n3:Context
rdf:value
ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles>>9<<, 16, further refined to infer directed (i.e. causal) interactions12, 22 (see Methods).
n3:mentions
n2:15778709
Subject Item
_:vb6691584
rdf:type
n3:Context
rdf:value
ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, >>16<<, further refined to infer directed (i.e. causal) interactions12, 22 (see Methods).
n3:mentions
n2:17114293
Subject Item
_:vb6691585
rdf:type
n3:Context
rdf:value
ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, 16, further refined to infer directed (i.e. causal) interactions>>12<<, 22 (see Methods).
n3:mentions
n2:17406294
Subject Item
_:vb6691586
rdf:type
n3:Context
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ARACNe is an information theoretic approach for the inference of TF-target interactions from large sets of gene expression profiles9, 16, further refined to infer directed (i.e. causal) interactions12, >>22<< (see Methods).
n3:mentions
n2:10802651
Subject Item
_:vb6691587
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ARACNe predicted 92,660 transcriptional interactions, 1,217 of which were between TFs and 102 of 149 MGES genes>>4<<, represented across all the gene expression profile data.
n3:mentions
n2:16530701
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_:vb6691588
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C/EBPβ and C/EBPδ were grouped as they form stoichiometric homo and heterodimers with identical DNA binding specificity and redundant transcriptional activity>>23<<. We thus use the term C/EBP to indicate the TF complex with the union of their targets as the corresponding regulon. Consistent with their previously reported activity24, 25, Spearman correlation analysis revealed that five of these TFs
n3:mentions
n2:12006103
Subject Item
_:vb6691589
rdf:type
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Consistent with their previously reported activity>>24<<, 25, Spearman correlation analysis revealed that five of these TFs are likely activators (Stat3, C/EBP, bHLH-B2, Runx1, and FosL2) and one is likely a repressor (ZNF238).
n3:mentions
n2:9756912
Subject Item
_:vb6691590
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Consistent with their previously reported activity24, >>25<<, Spearman correlation analysis revealed that five of these TFs are likely activators (Stat3, C/EBP, bHLH-B2, Runx1, and FosL2) and one is likely a repressor (ZNF238).
n3:mentions
n2:11350943
Subject Item
_:vb6691591
rdf:type
n5:Section
dc:title
validation of the mesenchymal regulatory module
n5:contains
_:vb6691592 _:vb6691593 _:vb6691594 _:vb6691595
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_:vb6691592
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We transduced v-myc immortalized mouse NSCs known as C17.>>226<<–28 as well as primary murine NSCs derived from the mouse telencephalon at embryonic day 13.5 with retroviruses expressing C/EBPβ and a constitutively active form of Stat3 (Stat3C)29.
n3:mentions
n2:17351625 n2:16737696 n2:15992799
Subject Item
_:vb6691593
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transduced v-myc immortalized mouse NSCs known as C17.226–28 as well as primary murine NSCs derived from the mouse telencephalon at embryonic day 13.5 with retroviruses expressing C/EBPβ and a constitutively active form of Stat3 (Stat3C)>>29<<. ShRNA-mediated silencing targeted C/EBPβ and Stat3 in the human glioma cell line SNB19 and in serum-free cultures of tumor cells derived from primary GBM that propel the formation of GBM-like tumors after intracranial transplantation in
n3:mentions
n2:10458605
Subject Item
_:vb6691594
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targeted C/EBPβ and Stat3 in the human glioma cell line SNB19 and in serum-free cultures of tumor cells derived from primary GBM that propel the formation of GBM-like tumors after intracranial transplantation in immunodeficient mice>>30<< (GBM-derived brain tumor initiating cells, GBM-BTICs, see Fig. 5c–g). We generated a global dataset of 89 individual samples, including 55 knockdown experiments in human glioma cells and 34 ectopic expression experiments in mouse NSCs.
n3:mentions
n2:16697959
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_:vb6691595
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The Atlas-TCGA dataset>>31<< includes 77 and 21 samples associated with worst- and best-prognosis, respectively (92 samples with intermediate prognosis were not considered).
n3:mentions
n2:18772890
Subject Item
_:vb6691596
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n5:Section
dc:title
c/ebpβ and stat3 are essential for mesenchymal transformation and glioma aggressiveness
n5:contains
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Finally, we conducted an immunohistochemical analysis for C/EBPβ and active, phospho-Stat3 in human tumor specimens, and compared their expression with that of YKL40 (a well-established mesenchymal protein expressed in primary human GBM)>>21<<, 32 and with patient outcome in a collection of 62 GBMs (Supplementary Fig. 9).
n3:mentions
n2:15753362
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_:vb6691598
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we conducted an immunohistochemical analysis for C/EBPβ and active, phospho-Stat3 in human tumor specimens, and compared their expression with that of YKL40 (a well-established mesenchymal protein expressed in primary human GBM)21, >>32<< and with patient outcome in a collection of 62 GBMs (Supplementary Fig. 9).
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