Dataset Information

Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation.

ABSTRACT: BACKGROUND: Sox10, a member of the Sry-related HMG-Box gene family, is a critical transcription factor for several important cell lineages, most notably the neural crest stem cells and the derivative peripheral glial cells and melanocytes. Thus far, only a handful of direct target genes are known for this transcription factor limiting our understanding of the biological network it governs. RESULTS: We describe identification of multiple direct regulatory target genes of Sox10 through a procedure based on function and conservation. By combining RNA interference technique and DNA microarray technology, we have identified a set of genes that show significant down-regulation upon introduction of Sox10 specific siRNA into Schwannoma cells. Subsequent comparative genomics analyses led to potential binding sites for Sox10 protein conserved across several mammalian species within the genomic region proximal to these genes. Multiple sites belonging to 4 different genes (proteolipid protein, Sox10, extracellular superoxide dismutase, and pleiotrophin) were shown to directly interact with Sox10 by chromatin immunoprecipitation assay. We further confirmed the direct regulation through the identified cis-element for one of the genes, extracellular superoxide dismutase, using electrophoretic mobility shift assay and reporter assay. CONCLUSION: In sum, the process of combining differential expression profiling and comparative genomics successfully led to further defining the role of Sox10, a critical transcription factor for the development of peripheral glia. Our strategy utilizing relatively accessible techniques and tools should be applicable to studying the function of other transcription factors.

SUBMITTER: Lee KE

PROVIDER: S-EPMC2556353 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation.

Lee Kyung Eun KE Nam Seungyoon S Cho Eun-ah EA Seong Ikjoo I Limb Jin-Kyung JK Lee Sanghyuk S Kim Jaesang J

BMC genomics 20080911

<h4>Background</h4>Sox10, a member of the Sry-related HMG-Box gene family, is a critical transcription factor for several important cell lineages, most notably the neural crest stem cells and the derivative peripheral glial cells and melanocytes. Thus far, only a handful of direct target genes are known for this transcription factor limiting our understanding of the biological network it governs.<h4>Results</h4>We describe identification of multiple direct regulatory target genes of Sox10 throug ...[more]

PMID: 18786246

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Project description:BackgroundEffects on gene expression due to environmental or genetic changes can be easily measured using microarrays. However, indirect effects on expression can be substantial. The indirect effects of a perturbation need to be distinguished from the direct effects if we are to understand the structure and behavior of regulatory networks.ResultsThe most direct way to perturb a transcriptional network is to alter transcription factor activity. Here, for the first time, we compare expression changes and genomic binding in a simple regulon under conditions of both low and high transcription factor activity. Specifically, we assessed the effects on expression and binding due to deletion of the yeast LEU3 transcription factor gene and effects due to elevation of Leu3 activity. Leu3 activity was elevated through overexpression and the introduction of a mutation that renders the protein constitutively active. Genes that are bound and/or regulated by Leu3 under one or both conditions were characterized in terms of their functional annotations and their predicted potential to be bound by Leu3. We also assessed the evolutionary conservation of the predicted binding potential using a novel alignment-independent method. Both perturbations yield genes that are likely to be direct targets of Leu3, including most of the classically defined targets. Additional direct targets are identified by each of the methods. However, experimental and computational criteria suggest that most genes whose expression is affected by the Leu3 genotype are unlikely to be regulated by binding of the protein.ConclusionMost genes that are differentially expressed by Leu3 are not direct targets despite the exceptional simplicity of the regulon, and the unusually direct nature of the perturbations investigated. These conclusions are reached through computational analyses that support and extend chromatin immunoprecipitation data on the identities of direct targets. These results have implications for the interpretation of expression experiments, especially in cases for which chromatin immunoprecipitation data are unavailable, incomplete, or ambiguous.

Dataset Information

Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation.

Publications

Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation.

Similar Datasets

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