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Exon expression profiling reveals stimulus-mediated exon use in neural cells

Adrienne E McKee1, Nicola Neretti23, Luis E Carvalho4, Clifford A Meyer56, Edward A Fox78, Alexander S Brodsky109* and Pamela A Silver1*

Author Affiliations

1 Department of Systems Biology, 200 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.

2 Department of Physics, Institute for Brain and Neural Systems, 182 Hope Street, Brown University, Providence, Rhode Island 02912, USA.

3 Center for Computational Molecular Biology, 115 Waterman Street, Brown University, Providence, Rhode Island 02912, USA.

4 Department of Applied Mathematics, 182 George Street, Brown University, Rhode Island 02912, USA.

5 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.

6 Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, USA.

7 Department of Medicine, 200 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.

8 Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.

9 Department of Molecular Biology, Cell Biology, and Biochemistry, 185 Meeting Street, Brown University, Providence, Rhode Island 02903, USA.

10 Center for Genomics & Proteomics, Center for Computational Molecular Biology, 70 Ship Street, Brown University, Providence, Rhode Island 02903, USA.

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Genome Biology 2007, 8:R159  doi:10.1186/gb-2007-8-8-r159

Published: 2 August 2007

Abstract

Background:

Neuronal cells respond to changes in intracellular calcium ([Ca2+]i) by affecting both the abundance and architecture of specific mRNAs. Although calcium-induced transcription and transcript variation have both been recognized as important sources of gene regulation, the interplay between these two phenomena has not been evaluated on a genome-wide scale.

Results:

Here, we show that exon-centric microarrays can be used to resolve the [Ca2+]i-modulated gene expression response into transcript-level and exon-level regulation. Global assessments of affected transcripts reveal modulation within distinct functional gene categories. We find that transcripts containing calcium-modulated exons exhibit enrichment for calcium ion binding, calmodulin binding, plasma membrane associated, and metabolic proteins. Additionally, we uncover instances of regulated exon use in potassium channels, neuroendocrine secretory proteins and metabolic enzymes, and demonstrate that regulated changes in exon expression give rise to distinct transcript variants.

Conclusion:

Our findings connect extracellular stimuli to specific exon behavior, and suggest that changes in transcript and exon abundance are reflective of a coordinated gene expression response to elevated [Ca2+]i. The technology we describe here lends itself readily to the resolution of stimulus-induced gene expression at both the transcript and exon levels.