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Developmental Biology - Epigenetics and Evolution
Cancers May Originate From Ancient Genes
Ancient, deactivated genes are now linked to human cancers...
Epigenetic change is a way to control DNA function without altering the DNA sequence. New research led by the Garvan Institute of Medical Research, Australia, joined by the Institute of Cell Biology, University of Münster, Germany, the Harry Perkins Institute of Medical Research, Australia and the Barcelona Institute for Science and Technology, Spain, suggests ancient, deactivated genes linked to human cancers may in fact have been shared and passed on between species for millions of years.
Silenced for most of their journey in humans, but sometimes activated.
New research has uncovered how some genes active in certain human cancers also exist in zebrafish, but in humans are 'silenced' or 'turned off' — hours after the human egg is fertilized. The Garvan study helps explain how epigenetics regulates genes, which are linked to cancer development in humans despite the long evolutionary distance between us, and in this instance, zebrafish. The research revealed significant differences between the zebrafish epigenome and human embryos, and may influence future studies on how epigenetic DNA is inherited.
"We show that we have conserved this embryonic event which switches off genes linked to cancers in humans. It's intriguing, yet we still don't know why it's happening. It suggests just how important to human health it is to keep these genes silenced."
Ozren Bogdanovic PhD, Head, Developmental Epigenomics Lab and study leader.
The findings appear in the journal Nature Communications.
An Unexpected Relative
At first glance, humans and zebrafish (a tiny fish species native to South Asia) hardly seem related - in fact, our common evolutionary ancestor dates back more than 400 million years. However, genetically, zebrafish and humans are not so different. We share around 70% of our protein-producing genes. The Garvan-led team set out to investigate how conserved are epigenetic changes that control how DNA is 'read' during development.
Genes are partly controlled by methylation - the placement of chemical 'tags' on sections of DNA to 'block' genes becomming active.
Researchers first isolated primordial germ cells — precursor cells to sperm and egg — in order to see how developing zebrafish embryos generate Whole Genome Bisulfite Sequencing (WGBS), a snapshot of all DNA methylation.
The Zebrafish Genome Has a Father Figure
They uncovered fundamental differences between methylation in mammals and zebrafish embryos. Zebrafish inherit active paternal DNA methylation patterns. Humans turn them off.
In the first week after fertilization, humans and other mammals 'reset' their DNA methylation patterns to allow for differentiation of unique tissue cell types. Then, in a second sweep occuring between the third and seventh week of development, embryo primordial germ cells are swept clean again allowing precursor cells to form as sperm and eggs.
Screening zebrafish embryo DNA over four stages of development, researchers found 68 genes turned off or methylated, within just 24 hours of being fertilized, inheriting active paternal methylation patterns.
"What was interesting is that most of these genes belong to a group called Cancer Testis Antigens. 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."
Ozren Bogdanovic PhD, Genomics and Epigenetics Division of Garvan Institute of Medical Research, and study leader.
Fresh Insight On An Ancient Mechanism
Genes that code for Cancer Testis Antigens (CTAs), are only active in the male testis and are turned off in all other human tissues. But, for unknown reasons, CTA genes get turned on again in some cancers — such as melanomas.
"Mammals and fish have very different strategies when it comes to developing an embryo," explains Bogdanovic. "But in spite of these differences, it appears that the control of CTA genes is conserved throughout evolution."
While this new work sheds light on human evolution, it may also potentially impact human health. Drugs that target CTAs are already being investigated as potential therapy for cancers.
This study provides more evidence for how significant CTAs are, and how tightly controlled they have been throughout evolution. However, It's unknown whether principles of epigenetic reset are evolutionarily conserved across all vertebrate species.
Abstract
Two waves of DNA methylation reprogramming occur during mammalian embryogenesis; during preimplantation development and during primordial germ cell (PGC) formation. However, it is currently unclear how evolutionarily conserved these processes are. Here we characterise the DNA methylomes of zebrafish PGCs at four developmental stages and identify retention of paternal epigenetic memory, in stark contrast to the findings in mammals. Gene expression profiling of zebrafish PGCs at the same developmental stages revealed that the embryonic germline is defined by a small number of markers that display strong developmental stage-specificity and that are independent of DNA methylation-mediated regulation. We identified promoters that are specifically targeted by DNA methylation in somatic and germline tissues during vertebrate embryogenesis and that are frequently misregulated in human cancers. Together, these detailed methylome and transcriptome maps of the zebrafish germline provide insight into vertebrate DNA methylation reprogramming and enhance our understanding of the relationships between germline fate acquisition and oncogenesis.
Authors
Ksenia Skvortsova, Katsiaryna Tarbashevich, Martin Stehling, Ryan Lister, Manuel Irimia, Erez Raz and Ozren Bogdanovic.
Acknowledgements
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Contributions
O.B. and E.R. designed the study. K.S., K.T., and R.L. contributed to concept and study design. Zebrafish work was performed by K.T. and E.R. M.S. performed FACS sorting of zebrafish PGCs. Methyl-seq and RNA-seq library preparation and sequencing was carried out by K.S. K.S. analysed the data with input from O.B. AS analysis was performed by M.I. K.S and O.B. wrote the manuscript with input from all authors. All authors discussed the results and commented on the manuscript.
Competing interests
The authors declare no competing interests.
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Jul 18 2019 Fetal Timeline Maternal Timeline News
 A study in zebrafish indicates that some genes linked to cancers in humans, are still active in the zebrafish embryo (above) and have been around throughout 400 million years of evolution. CREDIT Michael Geng PhD, Senior Research Officer.
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