Loss of the chromatin modifier Kdm2aa causes BrafV-600E -independent spontaneous melanoma in zebrafish
| Autor: | E. Elizabeth Patton, Zsofia Digby, Sonia Wojciechowska, John E. Collins, Richard White, Elisabeth M. Busch-Nentwich, Catherine M Scahill, ME Mathers, Derek L. Stemple, Till Bartke, Ian M Sealy |
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| Přispěvatelé: | Sealy, Ian M [0000-0002-2890-6635], White, Richard J [0000-0003-1842-412X], Bartke, Till [0000-0002-6584-2140], Busch-Nentwich, Elisabeth M [0000-0001-6450-744X], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Melanomas
0301 basic medicine Male Embryology Cancer Research Jumonji Domain-Containing Histone Demethylases Gene Expression KDM2A medicine.disease_cause Negative Staining Epigenesis Genetic Gene Knockout Techniques Medicine and Health Sciences Exome Zebrafish Melanoma Genetics (clinical) Staining Regulation of gene expression Genetics Chromosome Biology Fishes Cell Staining Animal Models Chromatin Gene Expression Regulation Neoplastic Oncology Experimental Organism Systems Osteichthyes Vertebrates Epigenetics Female Anatomy Research Article DNA Replication Proto-Oncogene Proteins B-raf lcsh:QH426-470 Biology Research and Analysis Methods 03 medical and health sciences Model Organisms Ocular System Journal Article medicine Gene silencing Animals RNA Messenger Molecular Biology Ecology Evolution Behavior and Systematics Sequence Analysis RNA Gene Expression Profiling Embryos Organisms Cancers and Neoplasms Biology and Life Sciences Cell Biology Zebrafish Proteins biology.organism_classification lcsh:Genetics Disease Models Animal 030104 developmental biology Specimen Preparation and Treatment Mutation biology.protein Eyes Demethylase Carcinogenesis Head Developmental Biology |
| Zdroj: | PLoS Genet. 13:e1006959 (2017) PLoS Genetics Scahill, C M, Digby, Z, Sealy, I M, Wojciechowska, S, White, R J, Collins, J E, Stemple, D L, Bartke, T, Mathers, M E, Patton, E E & Busch-Nentwich, E M 2017, ' Loss of the chromatin modifier Kdm2aa causes BrafV600E-independent spontaneous melanoma in zebrafish ', PLoS Genetics, vol. 13, no. 8, pp. e1006959 . https://doi.org/10.1371/journal.pgen.1006959 PLoS Genetics, Vol 13, Iss 8, p e1006959 (2017) PLOS Genetics |
| DOI: | 10.1371/journal.pgen.1006959 |
| Popis: | KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing. In addition to effects on translation and DNA replication gene expression, high-replicate RNA-seq in morphologically normal individuals demonstrates a stable regulatory response of epigenetic modifiers and the specific de-repression of a group of zinc finger genes residing in constitutive heterochromatin. Together our data reveal a complex role for Kdm2aa in regulating normal mRNA levels and carcinogenesis. These findings establish kdm2aa mutants as the first single gene knockout model of melanoma biology. Author summary Epigenetic modifications of DNA and histones, the major components of chromatin, play a central role in transcriptional regulation. KDM2A is a histone demethylase that integrates DNA and histone modification signatures and is involved in transcriptional silencing through heterochromatin maintenance. Here we show that adult zebrafish homozygous for the orthologue kdm2aa develop melanomas, a malignant form of skin cancer, independently from oncogenes known to drive melanoma formation. We observe that transcript abundance is widely affected in kdm2aa mutants and find that gene expression of several DNA- and histone- modifying enzymes is stably altered. We furthermore demonstrate a specific de-repression of a group of genes encoding zinc finger-containing proteins that has the potential to be involved in transcriptional regulation. We suggest that these molecular disruptions underlie the melanoma formation, as well as the other observed phenotypes such as reduced growth and survival, a male sex bias and an oogenesis defect. This work demonstrates in vivo a role for Kdm2aa as a tumour suppressor and establishes, to our knowledge, kdm2aa-deficient fish as the first single gene knockout vertebrate model of melanoma. |
| Databáze: | OpenAIRE |
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