SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus<i>MTMR2</i>

Fogarty, Elizabeth A.; Brewer, Megan H.; Rodríguez-Molina, José F.; Law, William D.; H., Ki; Steinberg, Noah; Svaren, John; Antonellis, Anthony

doi:10.1093/hmg/ddw233

Cited by 3 publications

(3 citation statements)

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“…4 d and e). Importantly, this shift toward higher sequence conservation supports the idea that these motifs carry greater functional importance and supports the utility of sequence conservation-based prioritization of SOX10 binding motifs [ 23 – 25 ]. As a whole, the increased SOX10 ChIP-Seq signal, increased number of SOX10 binding motifs, and higher conservation scores for motifs associated with SOX10-dependent TSSs are consistent with the regulation of these 265 TSSs by SOX10-responsive promoters.…”

Section: Resultssupporting

confidence: 64%

“…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 PNS myelination.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with the importance of SOX10 in activating gene promoters, multiple studies have described SOX10 binding directly at the promoters of myelin-related genes [ 16 , 20 – 22 ]. Furthermore, certain loci harbor SOX10-regulated alternative promoters that direct the expression of unique transcript and protein isoforms [ 23 – 25 ]. These findings raise important questions about isoform specificity at these loci and about the roles of the SOX10-regulated gene products in Schwann cell function.…”

Section: Introductionmentioning

confidence: 99%

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SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells

2020

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Background 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. 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. Results We 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. Conclusions In 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.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells

2020

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KLF6 Super-enhancer Regulates Cell Proliferation by Recruiting GATA2 and SOX10 in Human Hepatoma Cells

Kim³

et al. 2022

Mol Biol

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Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation

et al. 2016

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BackgroundThe transcription factor SOX10 is essential for all stages of Schwann cell development including myelination. SOX10 cooperates with other transcription factors to activate the expression of key myelin genes in Schwann cells and is therefore a context-dependent, pro-myelination transcription factor. As such, the identification of genes regulated by SOX10 will provide insight into Schwann cell biology and related diseases. While genome-wide studies have successfully revealed SOX10 target genes, these efforts mainly focused on myelinating stages of Schwann cell development. We propose that less-biased approaches will reveal novel functions of SOX10 outside of myelination.ResultsWe developed a stringent, computational-based screen for genome-wide identification of SOX10 response elements. Experimental validation of a pilot set of predicted binding sites in multiple systems revealed that SOX10 directly regulates a previously unreported alternative promoter at SOX6, which encodes a transcription factor that inhibits glial cell differentiation. We further explored the utility of our computational approach by combining it with DNase-seq analysis in cultured Schwann cells and previously published SOX10 ChIP-seq data from rat sciatic nerve. Remarkably, this analysis enriched for genomic segments that map to loci involved in the negative regulation of gliogenesis including SOX5, SOX6, NOTCH1, HMGA2, HES1, MYCN, ID4, and ID2. Functional studies in Schwann cells revealed that: (1) all eight loci are expressed prior to myelination and down-regulated subsequent to myelination; (2) seven of the eight loci harbor validated SOX10 binding sites; and (3) seven of the eight loci are down-regulated upon repressing SOX10 function.ConclusionsOur computational strategy revealed a putative novel function for SOX10 in Schwann cells, which suggests a model where SOX10 activates the expression of genes that inhibit myelination during non-myelinating stages of Schwann cell development. Importantly, the computational and functional datasets we present here will be valuable for the study of transcriptional regulation, SOX protein function, and glial cell biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3167-3) contains supplementary material, which is available to authorized users.

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SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locusMTMR2

Cited by 3 publications

References 51 publications

SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells

SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells

KLF6 Super-enhancer Regulates Cell Proliferation by Recruiting GATA2 and SOX10 in Human Hepatoma Cells

Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation

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