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Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest

ABSTRACT: We analyzed the epigenetic landscape of five bulk (unsorted) melanoma tumors in a zebrafish melanoma model using ATAC-seq. We find that areas of open chromatin are consistent between tumor samples.

ORGANISM(S): Danio rerio

PROVIDER: GSE145551 | GEO | 2021/06/01

REPOSITORIES: GEO

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Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development.

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.

| S-EPMC8184803 | biostudies-literature

Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest

Project description:Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest

| PRJNA607534 | ENA

Identification of neural crest and glial enhancers at the mouse Sox10 locus through transgenesis in zebrafish.

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.

| S-EPMC2518861 | biostudies-literature

A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation [zebrafish ChIP-seq]

Project description:We report the distribution of H3K27Ac histone marks in a zebrafish melanoma cell line and a zebrafish primary melanoma tumor with the aim of identifying super-enhancer regions and regions of interest. We also report sox10 ChIP-Seq on the same zebrafish melanoma cell line.

2016-02-01 | GSE75353 | GEO

Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation.

Project description:CHD7 mutations are implicated in a majority of cases of the congenital disorder, CHARGE syndrome. CHARGE, an autosomal dominant syndrome, is known to affect multiple tissues including eye, heart, ear, craniofacial nerves and skeleton and genital organs. Using a morpholino-antisense-oligonucleotide-based zebrafish model for CHARGE syndrome, we uncover a complex spectrum of abnormalities in the neural crest and the crest-derived cell types. We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice and differentiation and we suggest that sox10 deregulation is an important driver of the neural crest-derived aspects of Chd7 dependent CHARGE syndrome.

| S-EPMC5179949 | biostudies-literature

A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation [ATAC-Seq]

Project description:We report the locations of accessible/open chromatin as assayed by ATAC-Seq on two zebrafish melanoma cell lines, zcrest 1 and zcrest 2.

2016-02-01 | GSE75351 | GEO

A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation.

Project description:The "cancerized field" concept posits that cancer-prone cells in a given tissue share an oncogenic mutation, but only discreet clones within the field initiate tumors. Most benign nevi carry oncogenic BRAF(V600E) mutations but rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and specifically reexpressed in melanoma. Live imaging of transgenic zebrafish crestin reporters shows that within a cancerized field (BRAF(V600E)-mutant; p53-deficient), a single melanocyte reactivates the NCP state, revealing a fate change at melanoma initiation in this model. NCP transcription factors, including sox10, regulate crestin expression. Forced sox10 overexpression in melanocytes accelerated melanoma formation, which is consistent with activation of NCP genes and super-enhancers leading to melanoma. Our work highlights NCP state reemergence as a key event in melanoma initiation.

| S-EPMC4868069 | biostudies-literature

A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation [human cell line ChIP-seq]

Project description:We report the distribution of H3K27Ac histone marks in multiple human melanoma cell lines with the aim of identifying super-enhancer regions and regions of interest. Also performed ChipSeq for H3K4Me1 to identify active enhancers in a representative human melanoma cell line, A375.

2016-02-01 | GSE75352 | GEO

A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation [human cell line RNA-seq]

Project description:We report gene expression data for human melanoma cell lines using RNAseq.

2016-02-01 | GSE75354 | GEO

SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer.

Project description:BackgroundThe ERBB3 gene is essential for the proper development of the neural crest (NC) and its derivative populations such as Schwann cells. As with all cell fate decisions, transcriptional regulatory control plays a significant role in the progressive restriction and specification of NC derived lineages during development. However, little is known about the sequences mediating transcriptional regulation of ERBB3 or the factors that bind them.ResultsIn this study we identified three transcriptional enhancers at the ERBB3 locus and evaluated their regulatory potential in vitro in NC-derived cell types and in vivo in transgenic zebrafish. One enhancer, termed ERBB3_MCS6, which lies within the first intron of ERBB3, directs the highest reporter expression in vitro and also demonstrates epigenetic marks consistent with enhancer activity. We identify a consensus SOX10 binding site within ERBB3_MCS6 and demonstrate, in vitro, its necessity and sufficiency for the activity of this enhancer. Additionally, we demonstrate that transcription from the endogenous Erbb3 locus is dependent on Sox10. Further we demonstrate in vitro that Sox10 physically interacts with that ERBB3_MCS6. Consistent with its in vitro activity, we also show that ERBB3_MCS6 drives reporter expression in NC cells and a subset of its derivative lineages in vivo in zebrafish in a manner consistent with erbb3b expression. We also demonstrate, using morpholino analysis, that Sox10 is necessary for ERBB3_MCS6 expression in vivo in zebrafish.ConclusionsTaken collectively, our data suggest that ERBB3 may be directly regulated by SOX10, and that this control may in part be facilitated by ERBB3_MCS6.

| S-EPMC3124416 | biostudies-literature

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