Abstract

BackgroundMulticellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms. Schwann cells—the myelinating cells of the peripheral nervous system (PNS)—exhibit a specialized gene expression profile directed by the transcription factor SOX10, which is essential for PNS myelination. SOX10 regulates promoter elements associated with unique TSSs and gene isoforms at several target loci, implicating SOX10-mediated, isoform-specific gene expression in Schwann cell function. Here, we report on genome-wide efforts to identify SOX10-regulated promoters and TSSs in Schwann cells to prioritize genes and isoforms for further study.ResultsWe performed global TSS analyses and mined previously reported ChIP-seq datasets to assess the activity of SOX10-bound promoters in three models: (i) an adult mammalian nerve; (ii) differentiating primary Schwann cells, and (iii) cultured Schwann cells with ablated SOX10 function. We explored specific characteristics of SOX10-dependent TSSs, which provides confidence in defining them as SOX10 targets. Finally, we performed functional studies to validate our findings at four previously unreported SOX10 target loci: ARPC1A, CHN2, DDR1, and GAS7. These findings suggest roles for the associated SOX10-regulated gene products in PNS myelination.ConclusionsIn sum, we provide comprehensive computational and functional assessments of SOX10-regulated TSS use in Schwann cells. The data presented in this study will stimulate functional studies on the specific mRNA and protein isoforms that SOX10 regulates, which will improve our understanding of myelination in the peripheral nerve.

Highlights

  • Multicellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms

  • SRY-box transcription factor 10 (SOX10) binds to promoters in Schwann cells in vivo In Schwann cells, SOX10 regulates the promoters of critical myelin genes including loci that harbor more than one transcription start site (TSS) [16, 20, 21, 23]

  • This suggests that genome-wide characterization of SOX10 activity at promoter elements will reveal gene products important for peripheral nervous system (PNS) myelination

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Summary

Introduction

Multicellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms. Schwann cells—the myelinating cells of the peripheral nervous system (PNS)—exhibit a specialized gene expression profile directed by the transcription factor SOX10, which is essential for PNS myelination. SOX10 regulates promoter elements associated with unique TSSs and gene isoforms at several target loci, implicating SOX10-mediated, isoform-specific gene expression in Schwann cell function. We report on genome-wide efforts to identify SOX10-regulated promoters and TSSs in Schwann cells to prioritize genes and isoforms for further study. The complexity of the mammalian genome—in particular the expression of multiple, unique products from a single locus—is critical for the development and function of specialized cell types. This complexity is realized through a variety of mechanisms including alternative splicing, alternative start codon usage, alternative. Identifying and characterizing genes important for PNS myelination is necessary for a more complete understanding of Schwann cell function and related human diseases

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