Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest
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ABSTRACT:
PROVIDER: PRJNA607534 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11113213_1.fastq.gz | Fastqsanger.gz | |||
| SRR11113213_2.fastq.gz | Fastqsanger.gz | |||
| SRR11113214_1.fastq.gz | Fastqsanger.gz | |||
| SRR11113214_2.fastq.gz | Fastqsanger.gz | |||
| SRR11113215_1.fastq.gz | Fastqsanger.gz |
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Project description:The role of a neural crest developmental transcriptional program, which critically involves Sox10 upregulation, is a key conserved aspect of melanoma initiation in both humans and zebrafish, yet transcriptional regulation of sox10 expression is incompletely understood. Here we used ATAC-Seq analysis of multiple zebrafish melanoma tumors to identify recurrently open chromatin domains as putative melanoma-specific sox10 enhancers. Screening in vivo with EGFP reporter constructs revealed 9 of 11 putative sox10 enhancers with embryonic activity in zebrafish. Focusing on the most active enhancer region in melanoma, we identified a region 23 kilobases upstream of sox10, termed peak5, that drives EGFP reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A ~200 base pair region, conserved in Cyprinidae, within peak5 is required for transgenic reporter activity in neural crest and melanoma. This region contains dimeric SoxE/Sox10 dimeric binding sites essential for peak5 neural crest and melanoma activity. We show that deletion of the endogenous peak5 conserved genomic locus decreases embryonic sox10 expression and disrupts adult stripe patterning in our melanoma model background. Our work demonstrates the power of linking developmental and cancer models to better understand neural crest identity in melanoma.
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2012-06-05 | E-TABM-748 | biostudies-arrayexpress
Project description:Here, control human pluripotent stem cells (hiPSCs) and SOX10 knockout (SOX10 KO) hiPSCs were induced to differentiate to neural crest stem cells (NCSCs). We sequenced mRNA samples of differentiated cells at day 7 during NCSC differentiation to generate the gene expression profiles of these cells.
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Project description:Sox10 is a dynamically regulated transcription factor gene that is essential for the development of neural crest-derived and oligodendroglial populations. Developmental genes often require multiple regulatory sequences that integrate discrete and overlapping functions to coordinate their expression. To identify Sox10 cis-regulatory elements, we integrated multiple model systems, including cell-based screens and transposon-mediated transgensis in zebrafish, to scrutinize mammalian conserved, noncoding genomic segments at the mouse Sox10 locus. We demonstrate that eight of 11 Sox10 genomic elements direct reporter gene expression in transgenic zebrafish similar to patterns observed in transgenic mice, despite an absence of observable sequence conservation between mice and zebrafish. Multiple segments direct expression in overlapping populations of neural crest derivatives and glial cells, ranging from pan-Sox10 and pan-neural crest regulatory control to the modulation of expression in subpopulations of Sox10-expressing cells, including developing melanocytes and Schwann cells. Several sequences demonstrate overlapping spatial control, yet direct expression in incompletely overlapping developmental intervals. We were able to partially explain neural crest expression patterns by the presence of head to head SoxE family binding sites within two of the elements. Moreover, we were able to use this transcription factor binding site signature to identify the corresponding zebrafish enhancers in the absence of overall sequence homology. We demonstrate the utility of zebrafish transgenesis as a high-fidelity surrogate in the dissection of mammalian gene regulation, especially those with dynamically controlled developmental expression.
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Project description:Waardenburg syndrome (WS) is a autosomal dominant inherited disorder characterized by sensorineural hearing loss (SNHL) and pigment abnormalities. SOX10 is one of its main pathogenicity genes. In vitro generation of patient-specific induced pluripotent stem cells (iPSCs) is an effective approach for exploring the mechanisms of human disease. Here, we established an iPSCs from a WS patient with SOX10 mutation and differentiated it into induced neural crest cells (NCCs), the key cell type involves in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. We then performed high-throughput RNA-seq and examined the transcriptional misregulation at each stage. The transcriptome analysis differentiated NCCs reveals widespread gene expression changes and the differentially expressed genes(DEGs) were enriched with gene ontology (GO) of neuron migration, skeletal system development, multicellular organism development, which indicate the important role of SOX10 plays in the differentiation of NCCs. It's worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes related to the inner ear morphogenesis. Based on protein-protein interaction（PPI）net work, we selected four candidate genes that may be regulated by SOX10 in inner ear development: BMP2, LGR5, GBX2 and GATA3. In conclusion, the SOX10 deficiency in this WS patient has a significant impact on the gene expression patterns during the development of NCCs. The DEGs most significantly enriched the inner ear development and morphogenesis could help explain the underlying basis for the inner ear malformation seen in WS patient.
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