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Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M - Mol. Syst. Biol. (2014)

Bottom Line: Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center.RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells.Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus

Cell-type expression of module #13 in oligodendrocytesImmunohistochemistry analysis in the corpus callosum. Staining of LRP2 in the human corpus callosum reveals that the major cell population in the corpus callosum is the oligodendrocytes (the blue round nuclei), which express LRP2 stained in brown. A zoom-in view is shown in the inset.Neural cell-type expression of the orthologous module #13 in mouse brain. Gene expression in different neural cell types was hierarchically clustered into the three major cell types in brain (neurons, oligodendrocytes and astrocytes). The clustering grouped genes in module #13 into a neuron cluster and a glial cluster, enriched for Group 1 and 2 genes, respectively. The fraction of Group 1 (red) and 2 (blue) genes in the glial and neuronal clusters were represented by the pie charts, with statistical significance determined by a chi-square test.Overall expression of module #13 in cultured oligodendrocyte precursor cells (OPCs). Group 1 and 2 were expressed at a similar level as the transcriptome background in OPCs. The statistical significance was determined by Wilcoxon rank-sum test, and the error bars represent one standard error.The role of the module in oligodendrocyte (OL) development. Differentiation of OPCs into mature myelinating OLs (MOG+) led to a significant up-regulation of Group 1 genes (left, OPCs → mature OLs). On the other hand, conditional knockout (CKO) of the master myelination factor MRF from mature OLs led to a significant up-regulation of Group 2 genes (right, mature OLs → MRF CKO). The statistical significance was determined by Wilcoxon rank-sum test.A proposed model. Up-regulation is associated with, or likely to contribute to, the differentiation of OPCs into mature myelinating OLs. The mature OLs acquire their myelination capacity by activating the MRF-mediated regulatory network, which also serves to repress expression of Group 2 genes.
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fig04: Cell-type expression of module #13 in oligodendrocytesImmunohistochemistry analysis in the corpus callosum. Staining of LRP2 in the human corpus callosum reveals that the major cell population in the corpus callosum is the oligodendrocytes (the blue round nuclei), which express LRP2 stained in brown. A zoom-in view is shown in the inset.Neural cell-type expression of the orthologous module #13 in mouse brain. Gene expression in different neural cell types was hierarchically clustered into the three major cell types in brain (neurons, oligodendrocytes and astrocytes). The clustering grouped genes in module #13 into a neuron cluster and a glial cluster, enriched for Group 1 and 2 genes, respectively. The fraction of Group 1 (red) and 2 (blue) genes in the glial and neuronal clusters were represented by the pie charts, with statistical significance determined by a chi-square test.Overall expression of module #13 in cultured oligodendrocyte precursor cells (OPCs). Group 1 and 2 were expressed at a similar level as the transcriptome background in OPCs. The statistical significance was determined by Wilcoxon rank-sum test, and the error bars represent one standard error.The role of the module in oligodendrocyte (OL) development. Differentiation of OPCs into mature myelinating OLs (MOG+) led to a significant up-regulation of Group 1 genes (left, OPCs → mature OLs). On the other hand, conditional knockout (CKO) of the master myelination factor MRF from mature OLs led to a significant up-regulation of Group 2 genes (right, mature OLs → MRF CKO). The statistical significance was determined by Wilcoxon rank-sum test.A proposed model. Up-regulation is associated with, or likely to contribute to, the differentiation of OPCs into mature myelinating OLs. The mature OLs acquire their myelination capacity by activating the MRF-mediated regulatory network, which also serves to repress expression of Group 2 genes.

Mentions: To further validate our results, we performed immunohistochemical analyses for a Group 1 corpus callosum-specific gene (Supplementary Fig S10), LRP2, that also showed excessive mutation in our sequencing analyses (FigA). The experiment was performed in the frozen postmortem corpus callosum tissue from one autism patient (Fig4A) and one control subject (Supplementary Fig S11). LRP2 protein was significantly expressed in the corpus callosum in both individuals, with no obvious difference between the normal and ASD subjects. As shown in Fig4A, the staining results further revealed that the human corpus callosum was predominantly populated by oligodendrocyte cells.


Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M - Mol. Syst. Biol. (2014)

Cell-type expression of module #13 in oligodendrocytesImmunohistochemistry analysis in the corpus callosum. Staining of LRP2 in the human corpus callosum reveals that the major cell population in the corpus callosum is the oligodendrocytes (the blue round nuclei), which express LRP2 stained in brown. A zoom-in view is shown in the inset.Neural cell-type expression of the orthologous module #13 in mouse brain. Gene expression in different neural cell types was hierarchically clustered into the three major cell types in brain (neurons, oligodendrocytes and astrocytes). The clustering grouped genes in module #13 into a neuron cluster and a glial cluster, enriched for Group 1 and 2 genes, respectively. The fraction of Group 1 (red) and 2 (blue) genes in the glial and neuronal clusters were represented by the pie charts, with statistical significance determined by a chi-square test.Overall expression of module #13 in cultured oligodendrocyte precursor cells (OPCs). Group 1 and 2 were expressed at a similar level as the transcriptome background in OPCs. The statistical significance was determined by Wilcoxon rank-sum test, and the error bars represent one standard error.The role of the module in oligodendrocyte (OL) development. Differentiation of OPCs into mature myelinating OLs (MOG+) led to a significant up-regulation of Group 1 genes (left, OPCs → mature OLs). On the other hand, conditional knockout (CKO) of the master myelination factor MRF from mature OLs led to a significant up-regulation of Group 2 genes (right, mature OLs → MRF CKO). The statistical significance was determined by Wilcoxon rank-sum test.A proposed model. Up-regulation is associated with, or likely to contribute to, the differentiation of OPCs into mature myelinating OLs. The mature OLs acquire their myelination capacity by activating the MRF-mediated regulatory network, which also serves to repress expression of Group 2 genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4300495&req=5

fig04: Cell-type expression of module #13 in oligodendrocytesImmunohistochemistry analysis in the corpus callosum. Staining of LRP2 in the human corpus callosum reveals that the major cell population in the corpus callosum is the oligodendrocytes (the blue round nuclei), which express LRP2 stained in brown. A zoom-in view is shown in the inset.Neural cell-type expression of the orthologous module #13 in mouse brain. Gene expression in different neural cell types was hierarchically clustered into the three major cell types in brain (neurons, oligodendrocytes and astrocytes). The clustering grouped genes in module #13 into a neuron cluster and a glial cluster, enriched for Group 1 and 2 genes, respectively. The fraction of Group 1 (red) and 2 (blue) genes in the glial and neuronal clusters were represented by the pie charts, with statistical significance determined by a chi-square test.Overall expression of module #13 in cultured oligodendrocyte precursor cells (OPCs). Group 1 and 2 were expressed at a similar level as the transcriptome background in OPCs. The statistical significance was determined by Wilcoxon rank-sum test, and the error bars represent one standard error.The role of the module in oligodendrocyte (OL) development. Differentiation of OPCs into mature myelinating OLs (MOG+) led to a significant up-regulation of Group 1 genes (left, OPCs → mature OLs). On the other hand, conditional knockout (CKO) of the master myelination factor MRF from mature OLs led to a significant up-regulation of Group 2 genes (right, mature OLs → MRF CKO). The statistical significance was determined by Wilcoxon rank-sum test.A proposed model. Up-regulation is associated with, or likely to contribute to, the differentiation of OPCs into mature myelinating OLs. The mature OLs acquire their myelination capacity by activating the MRF-mediated regulatory network, which also serves to repress expression of Group 2 genes.
Mentions: To further validate our results, we performed immunohistochemical analyses for a Group 1 corpus callosum-specific gene (Supplementary Fig S10), LRP2, that also showed excessive mutation in our sequencing analyses (FigA). The experiment was performed in the frozen postmortem corpus callosum tissue from one autism patient (Fig4A) and one control subject (Supplementary Fig S11). LRP2 protein was significantly expressed in the corpus callosum in both individuals, with no obvious difference between the normal and ASD subjects. As shown in Fig4A, the staining results further revealed that the human corpus callosum was predominantly populated by oligodendrocyte cells.

Bottom Line: Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center.RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells.Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus