Dataset Information

The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.

ABSTRACT: Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRAS(G12D)-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRAS(G12D) overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.

SUBMITTER: Albacker CE

PROVIDER: S-EPMC3660348 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.

Albacker Colleen E CE Storer Narie Y NY Langdon Erin M EM Dibiase Anthony A Zhou Yi Y Langenau David M DM Zon Leonard I LI

PloS one 20130521 5

Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRAS(G12D)-driven zebrafi ...[more]

PMID: 23705022

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Project description:Fluorescent-labeled zebrafish RAS-induced embryonal rhabdomyosarcoma (ERMS) were created to facilitate in vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in diverse cellular compartments. Using this strategy, we have identified a molecularly distinct ERMS cell subpopulation that expresses high levels of myf5 and is enriched for ERMS-propagating potential when compared with other tumor-derived cells. Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that tumor-propagating potential is confined to myf5+ERMS cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ERMS cells reside within an expanded satellite cell compartment, but by late stage ERMS, myf5+cells are dynamically reorganized into distinct regions separated from differentiated tumor cells. Human ERMS also contain distinct areas of differentiated and undifferentiated cells. Time-lapse imaging revealed that myf5+ERMS cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. This finding helps explain the clinical observation that Myogenin positivity correlates with poor clinical outcome in human ERMS and suggests that differentiated tumor cells play critical roles in metastasis. One-cell stage myf5-GFP/mylz2-mCherry fluorescent transgenic zebrafish were injected with rag2-kRAS12D. A subset of animals developed ERMS. Tumor cells were transplanted into syngeneic recipient animals that lacked fluorescent reporter expression. ERMS cell subfractions were isolated from transplant animals and purified cell populations obtained following two rounds of FACS. Sorted cells were 1) analyzed by microarray/RT-PCR and 2) transplanted at limiting dilution into syngeneic animals. These experiments confirm that zebrafish ERMS contain molecularly distinct cell subfractions that express high levels of myf5-GFP and exhibit difference in gene expression when compared to other ERMS cell subtypes. All four fluorescent-labeled cell populations were analyzed (n=2 tumors total).

Dataset Information

The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.

Publications

The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.

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