Epigenetic regulators Rbbp4 and Hdac1 are overexpressed in a zebrafish model of RB1 embryonal brain tumor, and are required for neural progenitor survival and proliferation

• Published in: Disease models & mechanisms Vol. 11; no. 6
• Main Authors: Schultz, Laura E, Haltom, Jeffrey A, Almeida, Maira P, Wierson, Wesley A, Solin, Staci L, Weiss, Trevor J, Helmer, Jordan A, Sandquist, Elizabeth J, Shive, Heather R, McGrail, Maura
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.06.2018; The Company of Biologists
• Subjects: Adults; Animals; Apoptosis; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cancer; Cell cycle; Cell division; Cell Proliferation - genetics; Cell Survival; CRISPR; Epigenesis, Genetic; Epigenetics; Gene expression; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Mutagenesis; Nervous system; Neural Stem Cells - metabolism; Retina; Retinoblastoma; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Retinoblastoma-Binding Protein 4 - genetics; Retinoblastoma-Binding Protein 4 - metabolism; Transcription factors; Tumors; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; CRISPR somatic targeting; Epigenetic regulators; Hdac1; Rbbp4; RB1 embryonal oligoneural brain tumor; Zebrafish; Neural progenitor
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.034124

In this study, we used comparative genomics and developmental genetics to identify epigenetic regulators driving oncogenesis in a zebrafish ( ) somatic-targeting model of RB1 mutant embryonal brain tumors. Zebrafish brain tumors caused by TALEN or CRISPR targeting are histologically similar to human central nervous system primitive neuroectodermal tumors (CNS-PNETs). Like the human oligoneural CNS-PNET subtype, zebrafish tumors show elevated expression of neural progenitor transcription factors , , and the receptor tyrosine kinase oncogene. Comparison of tumor and germline mutant larval transcriptomes shows that the altered oligoneural precursor signature is specific to tumor tissue More than 170 chromatin regulators were differentially expressed in tumors, including overexpression of chromatin remodeler components ( ) and ( ). Germline mutant analysis confirms that zebrafish , and are required during brain development. is necessary for neural precursor cell cycle exit and terminal differentiation, is required for survival of postmitotic precursors, and maintains proliferation of the neural stem cell/progenitor pool. We present an assay using somatic CRISPR targeting plus live imaging of histone-H2A.F/Z-GFP fusion protein in developing larval brain to rapidly test the role of chromatin remodelers in neural stem and progenitor cells. Our somatic assay recapitulates germline mutant phenotypes and reveals a dynamic view of their roles in neural cell populations. Our study provides new insight into the epigenetic processes that might drive pathogenesis in RB1 brain tumors, and identifies Rbbp4 and its associated chromatin remodeling complexes as potential target pathways to induce apoptosis in RB1 mutant brain cancer cells.This article has an associated First Person interview with the first author of the paper.