Biology subjects

Kramer, E. T.

Publications and source records attributed to Kramer, E. T..

2 recordsLinked to original sources

bioRxiv2022

Cross-species analysis reveals unique and shared roles of Sox9 and Sox10 (SOXE family) transcription factors in melanoma

SOX9 and SOX10 are two highly similar transcription factors with nearly 100% identity at their DNA binding domains. Both transcription factors play key but distinct roles in neural crest cell fate specification and melanoma formation. High expression of SOX9 and SOX10 appear to be mutually exclusive, with high SOX10 characteristic of proliferative melanoma and high SOX9 characteristic of metastatic melanoma. To further elucidate the role of SOX9 in melanoma, we over-express SOX9 in a zebrafish melanoma model and a human melanoma cell line. Analysis of tumor onset, binding dynamics, and transcriptional identities supports the notion of SOX9 driving a more mesenchymal signature, which is important for metastasis. Additionally, we identified a potential mechanism of SOX9 down-regulation via analysis of a functional and recurrent non-coding variant in human melanoma. Altogether, our results present a dosage-dependent role of SOX9 and, likely, SOX10 in the melanoma lifespan.

cancer biology↗

bioRxiv2020

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

The re-emergence of a neural crest transcriptional program, including Sox10 upregulation, is a key step in melanoma initiation in humans and zebrafish. We hypothesize that epigenetic regulation of sox10 modulates melanoma initiation. ATAC-Seq analysis of zebrafish melanoma tumors identifies recurrently open chromatin domains near sox10. Reporter constructs for each putative sox10 enhancer were examined in zebrafish embryos for neural crest activity and in stable transgenic lines for melanoma activity. One element, peak5 (23 kilobases upstream of sox10), 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 bp region, conserved across the Cyprinidae family (fish), is required for peak5 activity in neural crest and melanoma, and contains dimeric SoxE binding sites essential for neural crest activity. Our work identifies a novel melanoma transcriptional enhancer, expanding our knowledge of epigenetic regulation of neural crest identity in melanoma.

cancer biology↗