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gbb12005-sup-0001-Figure S1.pptPowerPoint presentation912KFigure S1: Strategy used for a hierarchical CGG modeling of brain development to aid design of drugs to treat autism and schizophrenia. (a) Input microarray data analysis and SOM clustering. (b) Extraction of differentially expressed genes from SOM CGGs. (c) Information Entropy during brain growth and development was calculated as a value reciprocal to system's organization level. (d) Enrichment of CGGs in conventional signaling pathways and processed controling cerebral cortex development. (e) Modular gene-transcription factor regulatory network. (f) Functional/disease assessment of modules and regulating TFs involved in neurodisorders. (g) Future pharmacophore development and drug design based on hierarchical modular TF–gene network analysis.
gbb12005-sup-0002-Figure S2.pptPowerPoint presentation251KFigure S2: Explanation of self-organized map (SOM) construction: the first-level SOM. Genes with the similar profiles are mapped in the same pixel of the SOM, creating CGGs. Genes with profiles that are close enough but differ by some margin are mapped in adjacent pixels. The four CGGs circled on the SOM (with SOM coordinates [10,16], [11,16], [10,17] and [11,17]), a close-up of which is shown in the center of the figure, have profiles similar in appearance to those seen on the charts for each CGG. The CGG's colors represent the average expression value of each CGG for a different time point (day P07 is shown). Each CGG contains different numbers of genes, and its intensity is calculated as the centroid C of a finite set of k points x1, x2, …, xk to find the average of the points of the set (see eqn 1). Then color the span of centroids was calculated and a color code was assigned to each CGG for each time point according to its centroid.
gbb12005-sup-0003-Figure S3.pptPowerPoint presentation234KFigure S3: Explanation of zone selection. Each CGG contained a different number of genes with folds exceeding the 2.5 threshold, ranging from every gene in the CGG to only one. The following percentages of genes within each CGG with an expression over the threshold were considered at length: 100%, 75%, 50%, 33%, 25% and 9%. There are: (1) 46 CGGs containing 447 genes, each of which consists 100% of genes with an expression fold above the threshold, (2) 64 CGGs containing 634 genes, each CGG with 75% of genes above the threshold, (3) 91 CGGs containing 789 genes, each CGG with 50% of genes (394 genes) above the threshold, (4) 112 CGGs containing 835 genes, each CGG with 33% of genes above the threshold, (5) 120 CGGs containing 930 genes, each CGG with 25% of genes above the threshold and 135 CGGs containing 1073 genes, each CGG with only 9% of genes above the threshold; (this is illustrated in the curve of the chart at top left corner of the figure). Because the 50% grouping was located at the inflexion point of the curve, further analysis was completed using this option. Mapping of these 50% CGGs into the SOM created five zones located in its different areas. The resulting figures are summarized in Table S1 and illustrated here. See details in Materials and Methods section.
gbb12005-sup-0004-Figure S4.pptPowerPoint presentation107KFigure S4: Correlations between human and rat cortex development. Using the method described in (Rice & Barone 2000), we created a plot of possible correspondence of the courses of rat and human cortex development. The horizontal axis – days of rat brain development; the vertical – days of human brain development. PC, postcoitum. The red star indicates the day of birth of the human child (approximately 270 days PC) that corresponds to day 47 PC of rat. In different terms we can say that first postnatal day P01 of human corresponds with some level of reliability to postnatal day P28 of rat. Approximately P90 day of human corresponds to the P34 of rat. The program (translatingtime.net gives the limit for rat translating 35 PC days). The rest is our extrapolation.
gbb12005-sup-0005-Figure S5.pptPowerPoint presentation112KFigure S5: Thirty coherent-gene groups SOM used for elucidation of signaling pathways and processes in the studied genes set.
gbb12005-sup-0006-Figure S6.pptPowerPoint presentation234KFigure S6: Canonical signaling pathways activity during development. The plots show the P values supporting the statement that the pathway is activated (−log(P value) = 3 corresponding to the P value = 0.001).The following signaling pathways are selected: (a) Notch, (b) fibroblast growth factor (FGF), (c) apoptosis, (d) neuregulin, (e) Myc-mediated apoptosis, (f) integrin, (g) axonal guidance, (h) NF-kB, (i) IGF1, (j) endothelin-1, (k) glutamate receptor in neurons, (l) GABA-receptor in neurins, (m) CREB in neurons and (n) G-beta-gamma in neurons
gbb12005-sup-0007-Figure S7.pptPowerPoint presentation429KFigure S7: Glutamate metabotropic receptors during cortex development. (a) Expression of different glutamate metabotropic receptors for rat cortex development. Maximum expression occurs on P07 for GRM2, P14 GRM7 and on P21–P90 for GRM2. (b) The gene network involved in GRM3. Courtesy of Ingenuity Systems, Inc., Redwood City, CA, USA.
gbb12005-sup-0008-Figure S8.pptPowerPoint presentation1098KFigure S8: Cortex development. Illustration of TF-gene networks from different zones for different days of development. The example shows that genes and TFs are upregulated in the zone 1 and downregulated in the zone 2 on prenatal day E17, while vicevesrsa on postnatal dayP30.
gbb12005-sup-0009-Figure S9.pptPowerPoint presentation3771KFigure S9: Transcription factor–gene networks for the zone 1. Red – genes (ovals) and TFs (triangles) with increased expression; green – with no significantly increase expression (TFs are colored only when they are present in the initial gene set). (a) The network for the day E16 of development. (b) The network for the day P30. (c) Close-up of the central part of the lower (10th) level TF-gene network for the day E16; highlighted blue are CGGs having two and more schizophrenia-related genes; light-blue – having at least one schizophrenia-related gene; highlighted yellow – schizophrenia-related TFs.
gbb12005-sup-0010-Figure S10.pptPowerPoint presentation646KFigure S10: Close-up of the CGG M27 in zone 1 for day E16 (Fig. S9a) showing that genes have a number of interrelations. Red ovals – upregulated genes, green – not upregulated.
gbb12005-sup-0011-Figure S11.pptPowerPoint presentation528KFigure S11: Gene network connecting the genes within the CGG M27, created using IPA® (Ingenuity Systems, Inc., Santa Clara, CA, USA).
gbb12005-sup-0012-Figure S12.pptPowerPoint presentation1598KFigure S12: Transcription factor–gene networks for zone 2. Red – genes and TFs with increased expression; green – with no significantly increase expression. (TFs are colored only when they are present in the initial gene set; ovals in CGGs – genes: red – upregulatetd, green – not upregulated). (a) The network for the day E16 of development. (b) The network for the day P30 of development.
gbb12005-sup-0013-Figure S13.pptPowerPoint presentation329KFigure S13: Predicted transcription factor binding sites for genes essential in early stages of brain development and evolutionarily conserved in human, mouse and rat; (a) 15-kb proximal promoter region is displayed, exons, introns, the transcription start site, repetitive elements, conserved sequence regions and transcription factor binding sites, are color-coded. (b) Close-up of transcription factor-binding sites on the genes is significant for early stages of brain development.
gbb12005-sup-0014-Figure S14.pptPowerPoint presentation185KFigure S14: Venn diagrams that show relationships between different sets of TFs included in hierarchical gene–TF networks (see examples in Figs 5 and 6) for zones 1–3 (see Fig. 1a and S8). (a) Venn diagram of sets of TFs for schizophrenia and autism; one can see that there are many common TFs involved. (b and c) Venn diagram for TFs derived from three zones on bottom (most comprehensive) level of the hierarchical networks: (b) schizophrenia-related TFs. (c) autism-related. See related tables of genes in Supporting Information.
gbb12005-sup-0015-TableS1.docWord document28KTable S1: Coherent gene group with at least 50% of differentially expressed genes with the folds greater than 2.5 threshold in the selected clusters.
gbb12005-sup-0016-TableS2.docWord document29KTable S2: Number of CGGs with differentially expressed genes (from Table S1) active in specific days of development.
gbb12005-sup-0017-TableS3.docWord document47KTable S3: Interactions between the genes from the CGG M27 in zone 1, SOM coordinates [10,1].
gbb12005-sup-0018-TableS4.docWord document41KTable S4: Transcription factors related to schizophrenia and ASD in zones 1–3 (Fig. 8a)
gbb12005-sup-0019-TableS5.docWord document36KTable S5: TFs related to schizophrenia in zones 1–3 (Fig. 8b)
gbb12005-sup-0020-TableS6.docWord document29KTable S6: TFs related to ASD in zones 1–3 (Fig. 8c)
gbb12005-sup-0021-TableS7.xlsExcel spreadsheet45KTable S7: Functions of the genes in the selected CGGs of cluster 1

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