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Identification of a set of genes showing regionally enriched expression in the mouse brain.

D'Souza CA, Chopra V, Varhol R, Xie YY, Bohacec S, Zhao Y, Lee LL, Bilenky M, Portales-Casamar E, He A, Wasserman WW, Goldowitz D, Marra MA, Holt RA, Simpson EM, Jones SJ - BMC Neurosci (2008)

Bottom Line: The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest.GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology.This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 570 West 7th Ave - Suite 100, Vancouver, BC, V5Z 4E6, Canada. cdsouza@bcgsc.ca

ABSTRACT

Background: The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest. Our goal was to first identify genes displaying regionally enriched expression in the mouse brain so that promoters designed from orthologous human genes can then be tested to drive reporter expression in a similar pattern in the mouse brain.

Results: We have utilized LongSAGE to identify regionally enriched transcripts in the adult mouse brain. As supplemental strategies, we also performed a meta-analysis of published literature and inspected the Allen Brain Atlas in situ hybridization data. From a set of approximately 30,000 mouse genes, 237 were identified as showing specific or enriched expression in 30 target regions of the mouse brain. GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology.

Conclusion: Using a multi-faceted expression validation approach, we have identified mouse genes whose human orthologs are good candidates for design of mini-promoters. These mouse genes represent molecular markers in several discrete brain regions/cell-types, which could potentially provide a mechanistic explanation of unique functions performed by each region. This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

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Related in: MedlinePlus

Transcriptome similarity among 17 brain tissues based on expression divergence at P value = 0.01. Tissues being compared are indicated on the Y-axis, and expression divergence (EDP) of clusters of tissues is plotted on the X-axis. At each node in the dendrogram, the number of genes shared between libraries in the tissue cluster is indicated. A threshold of 50% of maximum EDP was chosen for coloring of branch lines in the dendrogram.
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Figure 2: Transcriptome similarity among 17 brain tissues based on expression divergence at P value = 0.01. Tissues being compared are indicated on the Y-axis, and expression divergence (EDP) of clusters of tissues is plotted on the X-axis. At each node in the dendrogram, the number of genes shared between libraries in the tissue cluster is indicated. A threshold of 50% of maximum EDP was chosen for coloring of branch lines in the dendrogram.

Mentions: We also analyzed SAGE data to measure transcriptome similarity between selected tissues. The premise was that tissues would cluster together or diverge based on the degree to which their genes are differentially expressed. Hierarchical clustering was done based on unweighted average distance between formed clusters (see description in Methods), the results of which are displayed in the form of a dendrogram (Figure 2). A pattern of divergent tissue clusters consistently emerges: a cluster of neuronal tissues and several discrete single tissue clusters including Ependymal Layers, Cerebellum White Matter and Cerebellum Purkinje Cell Layer. Among neuronal tissues, the Ventral and Medial Thalamus consistently clustered tightly together and had the lowest expression divergence between any two pairs of tissues. Additionally, Visual Cortex, Primary Motor Cortex, Amygdala (basolateral), Amygdala (central), and Dorsal Striatum also clustered together. Segregation of the Ependymal tissue into a separate single cluster makes sense given its non-neuronal nature [17], and the Cerebellar White Matter is composed of myelinated axonal processes. Clustering is usually sensitive to the specific expression divergence measure used. However, we tried several empirical measures, as well as different P values for selecting differentially expressed genes, and observed that the main pattern of clustering outlined above remains unchanged.


Identification of a set of genes showing regionally enriched expression in the mouse brain.

D'Souza CA, Chopra V, Varhol R, Xie YY, Bohacec S, Zhao Y, Lee LL, Bilenky M, Portales-Casamar E, He A, Wasserman WW, Goldowitz D, Marra MA, Holt RA, Simpson EM, Jones SJ - BMC Neurosci (2008)

Transcriptome similarity among 17 brain tissues based on expression divergence at P value = 0.01. Tissues being compared are indicated on the Y-axis, and expression divergence (EDP) of clusters of tissues is plotted on the X-axis. At each node in the dendrogram, the number of genes shared between libraries in the tissue cluster is indicated. A threshold of 50% of maximum EDP was chosen for coloring of branch lines in the dendrogram.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483290&req=5

Figure 2: Transcriptome similarity among 17 brain tissues based on expression divergence at P value = 0.01. Tissues being compared are indicated on the Y-axis, and expression divergence (EDP) of clusters of tissues is plotted on the X-axis. At each node in the dendrogram, the number of genes shared between libraries in the tissue cluster is indicated. A threshold of 50% of maximum EDP was chosen for coloring of branch lines in the dendrogram.
Mentions: We also analyzed SAGE data to measure transcriptome similarity between selected tissues. The premise was that tissues would cluster together or diverge based on the degree to which their genes are differentially expressed. Hierarchical clustering was done based on unweighted average distance between formed clusters (see description in Methods), the results of which are displayed in the form of a dendrogram (Figure 2). A pattern of divergent tissue clusters consistently emerges: a cluster of neuronal tissues and several discrete single tissue clusters including Ependymal Layers, Cerebellum White Matter and Cerebellum Purkinje Cell Layer. Among neuronal tissues, the Ventral and Medial Thalamus consistently clustered tightly together and had the lowest expression divergence between any two pairs of tissues. Additionally, Visual Cortex, Primary Motor Cortex, Amygdala (basolateral), Amygdala (central), and Dorsal Striatum also clustered together. Segregation of the Ependymal tissue into a separate single cluster makes sense given its non-neuronal nature [17], and the Cerebellar White Matter is composed of myelinated axonal processes. Clustering is usually sensitive to the specific expression divergence measure used. However, we tried several empirical measures, as well as different P values for selecting differentially expressed genes, and observed that the main pattern of clustering outlined above remains unchanged.

Bottom Line: The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest.GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology.This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 570 West 7th Ave - Suite 100, Vancouver, BC, V5Z 4E6, Canada. cdsouza@bcgsc.ca

ABSTRACT

Background: The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest. Our goal was to first identify genes displaying regionally enriched expression in the mouse brain so that promoters designed from orthologous human genes can then be tested to drive reporter expression in a similar pattern in the mouse brain.

Results: We have utilized LongSAGE to identify regionally enriched transcripts in the adult mouse brain. As supplemental strategies, we also performed a meta-analysis of published literature and inspected the Allen Brain Atlas in situ hybridization data. From a set of approximately 30,000 mouse genes, 237 were identified as showing specific or enriched expression in 30 target regions of the mouse brain. GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology.

Conclusion: Using a multi-faceted expression validation approach, we have identified mouse genes whose human orthologs are good candidates for design of mini-promoters. These mouse genes represent molecular markers in several discrete brain regions/cell-types, which could potentially provide a mechanistic explanation of unique functions performed by each region. This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

Show MeSH
Related in: MedlinePlus