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

Lee, Jun Young; Nam, Seungyoon; Cho, Eun Ah; Seong, Ikjoo; Limb, Jin Kyung; Lee, Sanghyuk; Kim, Jaesang

doi:10.1186/1471-2164-9-408

Cited by 31 publications

(23 citation statements)

References 37 publications

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“…SOX10, in synergy with its known cofactors, could also induce Ret or Ednrb expression (Lang et al, 2000;Lang and Epstein, 2003;Zhu et al, 2004) and subsequent RET-or EDNRB-β1-integrins dependent signaling cascades (Cockburn et al, 2010;Lange et al, 2007) and thus control cell migration. Finally, SOX10 has recently been shown to regulate other genes involved in migratory processes, some of them expressed in gut and interacting with components of β1-integrins signaling pathways (Finzsch et al, 2008;King et al, 2011;Lee et al, 2008;Veevers-Lowe et al, 2010;You and Lin-Chao, 2010). The defects observed could therefore be due to changes in crosstalk mediated by these genes.…”

Section: Discussionmentioning

confidence: 94%

Sox10 and Itgb1 interaction in enteric neural crest cell migration

Watanabe

Broders-Bondon

Baral

et al. 2013

Developmental Biology

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SOX10 involvement in syndromic form of Hirschsprung disease (intestinal aganglionosis, HSCR) in humans as well as developmental defects in animal models highlight the importance of this transcription factor in control of the pool of enteric progenitors and their differentiation. Here, we characterized the role of SOX10 in cell migration and its interactions with β1-integrins. To this end, we crossed the Sox10(lacZ/+) mice with the conditional Ht-PA::Cre; beta1(neo/+) and beta1(fl/fl) mice and compared the phenotype of embryos of different genotypes during enteric nervous system (ENS) development. The Sox10(lacZ/+); Ht-PA::Cre; beta1(neo/fl) double mutant embryos presented with increased intestinal aganglionosis length and more severe neuronal network disorganization compared to single mutants. These defects, detected by E11.5, are not compensated after birth, showing that a coordinated and balanced interaction between these two genes is required for normal ENS development. Use of video-microscopy revealed that defects observed result from reduced migration speed and altered directionality of enteric neural crest cells. Expression of β1-integrins upon SOX10 overexpression or in Sox10(lacZ/+) mice was also analyzed. The modulation of SOX10 expression altered β1-integrins, suggesting that SOX10 levels are critical for proper expression and function of this adhesion molecule. Together with previous studies, our results strongly indicate that SOX10 mediates ENCC adhesion and migration, and contribute to the understanding of the molecular and cellular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 mutations.

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Section: Discussionmentioning

confidence: 94%

Sox10 and Itgb1 interaction in enteric neural crest cell migration

Watanabe

Broders-Bondon

Baral

et al. 2013

Developmental Biology

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“…These efforts, and others [32], have utilized a variety of experimental methodologies to identify putative SOX10 regulatory elements across diverse SOX10-positive tissues. While each approach uncovered novel SOX10 response elements, no single method has been successful in the identification of all SOX10 response elements.…”

Section: Discussionmentioning

confidence: 99%

“…We also searched for each gene name plus ‘Schwannoma’ in the GEO Profiles database at NCBI to determine if gene expression is depleted upon treatment with SOX10 siRNA [32]. …”

Section: Methodsmentioning

confidence: 99%

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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“…Although the approach has its limitations because not all conserved motifs are functional and not all functional motifs are conserved (Birney et al, 2007), genes such as Sox4 and Sox10 have been investigated successfully using this method (Lee et al, 2008;Liao et al, 2008). In an initial exploratory approach, we predicted at the genome-wide level conserved matches to two SOX9 motifs and one generic SOX site within the proximal promoters defined as the region À1 kb upstream of the transcription start site [see (Lardenois et al, 2010) for methods].…”

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confidence: 99%

Genome‐wide identification of Sox8‐, and Sox9‐dependent genes during early post‐natal testis development in the mouse

et al. 2013

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Genome-wide identification of Sox8-, and Sox9-dependent genes during early post-natal testis development in the mouse F. Chalmel,*,a A. Lardenois,*,a I. Georg, †, ‡,k F. Barrionuevo, †,** P. Demougin, § B. J egou,*, ¶ G. Scherer † and M. Primig* *Inserm, U1085-Irset, University of Rennes 1, Rennes, France, †Institute of Human Genetics, University of Freiburg, Freiburg, Germany, ‡Faculty for Biology, University of Freiburg, Freiburg, Germany, §Biozentrum, University of Basel, Basel, Switzerland, ¶EHESP School of Public Health (Rennes, Paris), Rennes Cedex, France, k Present address: Area of Human DNA Variability, Centro de Genomica e Investigacio Oncologica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain, and **Departamento de Genetica e Instituto de Biotecnologia, Universidad de Granada, Armilla, Spain SUMMARYThe SOX8 and SOX9 transcription factors are involved in, among others, sex differentiation, male gonad development and adult maintenance of spermatogenesis. Sox8 À/À mice lacking Sox9 in Sertoli cells fail to form testis cords and cannot establish spermatogenesis. Although genetic and histological data show an important role for these transcription factors in regulating spermatogenesis, it is not clear which genes depend upon them at a genome-wide level. To identify transcripts that respond to the absence of Sox8 in all cells and Sox9 in Sertoli cells we measured mRNA concentrations in testicular samples from mice at 0, 6 and 18 days post-partum. In total, 621 and 629 transcripts were found at decreased or increased levels, respectively, at different time points in the mutant as compared to the control samples. These mRNAs were categorized as preferentially expressed in Sertoli cells or germ cells using data obtained with male and female gonad samples and enriched testicular cell populations. Five candidate genes were validated at the protein level. Furthermore, we identified putative direct SOX8 and SOX9 target genes by integrating predicted SOX-binding sites present in potential regulatory regions upstream of the transcription start site. Finally, we used protein network data to gain insight into the effects on regulatory interactions that occur when Sox8 and Sox9 are absent in developing Sertoli cells. The integration of testicular samples with enriched Sertoli cells, germ cells and female gonads enabled us to broadly distinguish transcripts directly affected in Sertoli cells from others that respond to secondary events in testicular cell types. Thus, combined RNA profiling signals, motif predictions and network data identified putative SOX8/SOX9 target genes in Sertoli cells and yielded insight into regulatory interactions that depend upon these transcription factors. In addition, our results will facilitate the interpretation of genome-wide in vivo SOX8 and SOX9 DNA binding data.

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

Cited by 31 publications

References 37 publications

Sox10 and Itgb1 interaction in enteric neural crest cell migration

Sox10 and Itgb1 interaction in enteric neural crest cell migration

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

Genome‐wide identification of Sox8‐, and Sox9‐dependent genes during early post‐natal testis development in the mouse

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