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Review
. 2011 Jun;93(2):194-203.
doi: 10.1002/bdrc.20207.

Epigenetics, development, and cancer: zebrafish make their mark

Raksha Mudbhary  1 , Kirsten C Sadler
Affiliations
Review

Epigenetics, development, and cancer: zebrafish make their mark

Raksha Mudbhary et al. Birth Defects Res C Embryo Today. 2011 Jun.

Abstract

Zebrafish embryos are an exceptional system for studying vertebrate development. Historically, studies using zebrafish to uncover key players in developmentally regulated gene expression have entailed detailed analysis of transcription factors. It is now apparent that epigenetic modifications of both DNA and histone tails are equally important in the regulation of gene expression during development. As such, blocking the function of key epigenetic modifiers impairs development, albeit with surprising tissue specificity. For instance, DNA methylation is an important epigenetic mark that is depleted in embryos lacking dnmt1 and uhrf1. These embryos display developmental defects in the eye, liver, pancreas, and larval lethality. Interestingly, human tumors derived from these same organs have aberrant changes in DNA methylation and altered expression of genes that are thought to contribute to formation of these cancers. These observations have provided a mechanistic basis for treating cancer with drugs that block the enzymes that facilitate DNA and histone modifications. Thus, it is important to understand the consequences of targeting these factors in a whole animal. We review the use of zebrafish for probing the genetic, cellular, and physiological response to alterations in the epigenome and highlight exciting data illustrating that epigenetic studies using zebrafish can inform and impact cancer biology.

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Figures

Figure 1
Figure 1
Modifications of the tails of histones play an important role in regulating gene expression. This figure demonstrates some of the better studied histone modifications on the tails of H2A, H2B, H3, and H4. Those in green are activating marks, in red are repressive marks, and in gray are those that are unknown.
Figure 2
Figure 2
DNMT and HDAC inhibitors disrupt zebrafish embryogenesis and liver development. (A) Zebrafish embryos treated with VPA or 5-Aza develop small livers. VPA treatment starting at 6 hpf delayed the appearance of the liver on day 3 and resulted in 100% of the affected embryos displaying a small, ball-shaped liver. 5-Aza treatment at 1.5 hours resulted in 50% mortality (not shown). The majority of survivors (84%) display a smaller, misshapen liver. (B) Treatment of zebrafish embryos at 6 hpf with 20 μM VPA results in increased acetylated histone H3 (Ac-H3) at 5 dpf. (C) Treatment of zebrafish embryos with 5-Aza at 1.5 hpf results in a global loss of DNA methylation. The methylation sensitive (HpaII) and methylation insensitive (MspI) enzymes were used to assess changes in methylation levels in untreated and 5-Aza treated embryos. The smear in the HpaII lane of the 5-Aza treated embryos indicates increased digestion of the DNA, reflecting decreased methylation.
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