PUBLICATION
Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development
- Authors
- Cunningham, R.L., Kramer, E.T., DeGeorgia, S.K., Godoy, P.M., Zarov, A.P., Seneviratne, S., Grigura, V., Kaufman, C.K.
- ID
- ZDB-PUB-210609-6
- Date
- 2021
- Source
- Communications biology 4: 695 (Journal)
- Registered Authors
- Keywords
- none
- Datasets
- GEO:GSE145551
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Enhancer Elements, Genetic
- Gene Expression Regulation, Developmental
- Gene Expression Regulation, Neoplastic
- Melanoma/genetics*
- Neural Crest/embryology*
- Neural Crest/metabolism
- SOXE Transcription Factors/genetics*
- Zebrafish/embryology*
- Zebrafish/genetics*
- Zebrafish Proteins/genetics*
- PubMed
- 34099848 Full text @ Commun Biol
Citation
Cunningham, R.L., Kramer, E.T., DeGeorgia, S.K., Godoy, P.M., Zarov, A.P., Seneviratne, S., Grigura, V., Kaufman, C.K. (2021) Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development. Communications biology. 4:695.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping