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

dc.contributor.author Schultz, Laura
dc.contributor.author Haltom, Jeffrey
dc.contributor.author McGrail, Maura
dc.contributor.author Almeida, Maira
dc.contributor.author Wierson, Wesley
dc.contributor.author Solin, Staci
dc.contributor.author Weiss, Trevor
dc.contributor.author Helmer, Jordan
dc.contributor.author Sandquist, Elizabeth
dc.contributor.author Shive, Heather
dc.contributor.author McGrail, Maura
dc.contributor.department Genetics, Development and Cell Biology
dc.date 2019-02-07T00:46:05.000
dc.date.accessioned 2020-06-30T04:01:52Z
dc.date.available 2020-06-30T04:01:52Z
dc.date.copyright Mon Jan 01 00:00:00 UTC 2018
dc.date.issued 2018-01-01
dc.description.abstract <p>In this study, we used comparative genomics and developmental genetics to identify epigenetic regulators driving oncogenesis in a zebrafish <em>retinoblastoma 1</em> (<em>rb1</em>) somatic-targeting model of RB1 mutant embryonal brain tumors. Zebrafish <em>rb1</em> 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 <em>OLIG2+/SOX10+</em> CNS-PNET subtype, zebrafish <em>rb1</em> tumors show elevated expression of neural progenitor transcription factors <em>olig2</em>, <em>sox10</em>, <em>sox8b</em> and the receptor tyrosine kinase <em>erbb3a</em> oncogene. Comparison of <em>rb1</em> tumor and <em>rb1/rb1</em> germline mutant larval transcriptomes shows that the altered oligoneural precursor signature is specific to tumor tissue<strong>.</strong> More than 170 chromatin regulators were differentially expressed in <em>rb1</em> tumors, including overexpression of chromatin remodeler components <em>histone deacetylase 1</em> (<em>hdac1</em>) and <em>retinoblastoma binding protein 4</em>(<em>rbbp4</em>). Germline mutant analysis confirms that zebrafish <em>rb1</em>, <em>rbbp4</em> and <em>hdac1</em> are required during brain development. <em>rb1</em> is necessary for neural precursor cell cycle exit and terminal differentiation, <em>rbbp4</em> is required for survival of postmitotic precursors, and <em>hdac1</em> maintains proliferation of the neural stem cell/progenitor pool. We present an <em>in vivo</em> 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.</p>
dc.description.comments <p>This article is published as Schultz, Laura E., Jeffrey A. Haltom, Maira P. Almeida, Wesley A. Wierson, Staci L. Solin, Trevor J. Weiss, Jordan A. Helmer, Elizabeth J. Sandquist, Heather R. Shive, and Maura McGrail. "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." <em>Disease models & mechanisms</em> 11, no. 6 (2018): dmm034124. doi: <a href="https://doi.org/10.1242/dmm.034124" target="_blank">10.1242/dmm.034124</a>.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/gdcb_las_pubs/206/
dc.identifier.articleid 1210
dc.identifier.contextkey 13672715
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath gdcb_las_pubs/206
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/37879
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/gdcb_las_pubs/206/2018_McGrail_EpigeneticRegulators.pdf|||Fri Jan 14 22:26:28 UTC 2022
dc.source.uri 10.1242/dmm.034124
dc.subject.disciplines Cancer Biology
dc.subject.disciplines Cell and Developmental Biology
dc.subject.disciplines Genetics
dc.subject.disciplines Genomics
dc.subject.keywords Zebrafish
dc.subject.keywords Rbbp4
dc.subject.keywords Hdac1
dc.subject.keywords RB1 embryonal oligoneural brain tumor
dc.subject.keywords Epigenetic regulators
dc.subject.keywords CRISPR somatic targeting
dc.subject.keywords Neural progenitor
dc.title 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
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication 4881c673-9a87-4c3e-8a14-364a3de33be1
relation.isOrgUnitOfPublication 9e603b30-6443-4b8e-aff5-57de4a7e4cb2
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