A study in zebrafish indicates that some genes linked to cancers in humans have been strictly regulated throughout evolution. [Michael Geng]

Studies in zebrafish by a Garvan Institute of Medical Research-led team suggest that an epigenetic modification that switches off some cancer-associated genes has been conserved for more than 400 million years. The scientists discovered how genes that are turned on in some human cancers also exist in zebrafish, but are deactivated within hours of fertilization. Their study, reported in Nature Communications, provides new insights into how epigenetic regulation of genes—including those that are associated with the development of cancer in later life—can persist over large evolutionary distances. The findings also highlight key differences in how the epigenome resets itself during human and zebrafish embryogenesis, which could help to direct ongoing research into epigenetic inheritance.

“We’ve shown that we have conserved this embryonic event that switches off genes linked to cancers in humans,” said research lead Ozren Bogdanovic, PhD, head of the developmental epigenomics laboratory at the Garvan Institute. “It’s intriguing and we still don’t know why it’s happening, but it suggests just how important to human health it is to keep these genes silenced.” The scientists’ studies are reported in a paper titled “Retention of paternal DNA methylome in the developing zebrafish germline.”

Although zebrafish and humans diverged in evolutionary terms some 400 million years ago, the two species are genetically quite similar, and share about 70% of protein-coding genes. Whatever the species, vertebrate embryogenesis requires very tight control of when and where different genes are expressed. DNA methylation (5-methylcytosine, 5mC) and histone tail modifications are two epigenetic mechanisms that play a key role in that control. “The acquisition of these regulatory determinants defines key developmental stages and is implicated in processes such as pluripotency and cell differentiation,” the authors wrote.

What has previously been shown is that two waves of DNA methylation reprogramming occur during mammalian embryogenesis, the researchers continued. During mammalian preimplantation development and primordial germ cell (PGC) formation, the DNA methylome is effectively erased, and then gradually re-established. “In mammalian zygotes, the paternal genome is rapidly demethylated shortly after fertilization, followed by a progressive drop in 5mC of both paternal and maternal genomic contributions. DNA demethylation takes place up until the blastocyst stage followed by cell-type-specific remethylation during gastrulation.” The exact mechanism by which DNA demethylation occurs in the mammalian zygote does, however, “remain a topic of debate.”

Interestingly, zebrafish and other non-mammalian (anamniote) vertebrates don’t demonstrate this global 5mC eradication after fertilization. Zebrafish instead inherit their paternal DNA methylation configuration. The Garvan-led team wanted to look more closely at epigenetic changes that occur during embryongenesis, and identify whether such mechanisms might be conserved between zebrafish and mammals. They isolated primordial germ cells (PGCs) from developing zebrafish embryos, and carried out whole genome bisulfite sequencing (WGBS), to provide a snapshot of all the DNA methylation in these cells.

The initial findings confirmed that zebrafish PGCs inherit paternal DNA methylation patterns rather than completely resetting methylation patterns, which contrasts with the second “sweep cleaning” of DNA methylation tags during mammalian PGC development, the investigators pointed out. They analyzed WGBS and transcriptomic data derived from zebrafish PGCs and somatic cells during four stages of embryogenesis, and identified 68 genes that were methylated and so switched off within 24 hours of fertilization. “What was interesting is that most of these genes belong to a group called cancer testis antigens,” noted Ksenia Skvortsova, PhD, co-first author of the study and postdoctoral research fellow at Garvin. “Our work shows that these are some of the very first genes that are ‘silenced’, or targeted by DNA methylation, in both zebrafish and mammals.”

Such cancer testis antigens (CTAs) are active in the male testis, but in humans are normally turned off in all other tissues. “These genes display highly restricted patterns of somatic expression and are robustly expressed in the male germline,” the authors wrote. However, the CTA genes can be turned on again in some cancers. “CTAs are frequently reactivated in human cancers, including melanoma and breast cancer, where they are believed to contribute to specific features of the neoplastic phenotype, including invasiveness and metastatic capacity …. It remains to be determined whether this highly specific 5mC embryonic targeting has been conserved over such large evolutionary distances due to the deleterious effects that the somatic expression of these targets might have on cellular integrity.”

“Mammals and fish have very different strategies when it comes to developing an embryo,” noted Bogdanovic. “But in spite of these very different strategies, it appears that the control of CTA genes are conserved throughout evolution.”

The researchers suggest that their work provides “the missing link” in understanding how anamniote vertebrates program their developmental and germline epigenomes. The findings may also have implications for cancer research and therapeutics development. Drugs that target CTAs are already being investigated as a potential therapy for cancers, and the current study provides additional evidence about how significant CTAs are, and how tightly they have been controlled during evolution.

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